TWI867053B - Antiviral pyrazolopyridinone compounds - Google Patents

Abstract

The invention provides compounds of Formula (I)

Description

Antiviral pyrazolopyridone compounds

The present invention relates to novel bicyclic pyrazolopyridone compounds that are inhibitors of herpes virus replication and are thus useful in treating herpes virus infections. The compounds inhibit viral DNA polymerases of a variety of herpes viruses, including cytomegalovirus (CMV), herpes simplex virus, and others. The present invention provides novel bicyclic pyrazolopyridone compounds as disclosed herein, pharmaceutical compositions containing such compounds, and methods of using such compounds and compositions to treat and prevent herpes virus diseases.

Human CMV, also known as human herpesvirus 5 (HHV-5), is a beta-herpesvirus that affects all populations worldwide, including adults and children with normal or compromised immune systems. Although CMV is usually asymptomatic in healthy individuals, it can become life-threatening in immunocompromised individuals. CMV also causes concern during pregnancy because it can be transmitted from mother to fetus and cause severe birth defects. There are no treatments approved to prevent or treat congenital CMV infection. In the transplant setting, current anti-CMV therapies include the nucleoside analogs valganciclovir (valGCV), ganciclovir (GCV), and cidofovir (CDV), and the pyrophosphate analog foscarnet (FOS). Each of these therapeutic agents inhibits CMV DNA polymerase, a protein encoded by the UL54 gene, an enzyme essential for viral replication (PNAS 2003, 100(24), 14223-14228; WO2013/152063; WO 2005/012545). In solid organ transplant recipients, first-line therapy consists of prophylactic or preemptive therapy with GCV or the orally bioavailable prodrug valGCV. GCV significantly reduces disease risk and is effective in treating active CMV infection. However, the drug is poorly tolerated. GCV and valGCV can cause severe bone marrow suppression, which in stem cell transplant recipients puts patients at risk for transplant failure. Second-line therapies, such as CDV and FOS, are associated with severe renal toxicity. In addition, resistance to current anti-CMV nucleoside analogs is a major cause of treatment failure. Therefore, there is a need for novel classes of CMV therapeutics, in particular, non-nucleoside compounds, to provide safer CMV treatments and to combat herpes viruses that are resistant to known classes of antivirals.

In addition to CMV, herpes viruses that cause widespread human viral infections include Epstein-Barr virus (EBV), varicella zoster virus (VZV), and herpes simplex viruses HSV-1 and HSV-2. Other herpes viruses that cause human disease include human herpes virus-6, human herpes virus-7, and Kaposi's sarcoma-associated herpes virus.

Herpes virus infections are not only widespread, but they remain latent in the host throughout life. According to one estimate, more than 90% of adults are latently infected with at least one herpes virus, which may reactivate in subsequent years. For example, when the varicella zoster virus (VZV) reactivates from latency, it produces herpes zoster (Shingles), typically many years after the initial infection (chickenpox) has been controlled. Shingles is a painful condition that primarily affects the elderly and immunocompromised individuals. Complications include postherpetic neuralgia, a potentially debilitating and chronic pain syndrome that anti-VZV inhibitors (nucleosides) have only marginal effects on.

Immunocompromised individuals, such as transplant patients, face a high risk of reactivation of herpes viruses, such as CMV, HSV or VZV. Therefore, safe and potent viral inhibitors with broad herpes virus activity would be extremely valuable. The present invention provides novel compounds with activity against several herpes viruses, including CMV, HSV, VZV and EBV.

The present invention provides novel non-nucleoside compounds that inhibit herpes virus DNA polymerase with potent in vitro antiviral activity. The compounds have activity against several herpes viruses (including CMV, HSV, VZV and EBV). Potent non-nucleoside polymerase inhibitors have significant advantages over current anti-CMV drugs. First, unlike nucleoside analogs, the compounds are not incorporated by human polymerase and are therefore expected to have a better safety profile than current anti-CMV drugs. Secondly, the compounds described herein are active against GCV-resistant viruses and therefore have the potential for rescue therapy in patients with cross-resistance to nucleoside analogs. Finally, the compounds are active against several human herpes viruses, providing opportunities for widespread clinical use. The present invention also provides pharmaceutical compositions containing novel compounds, and methods of using the compounds and compositions to inhibit herpes virus replication or reactivation and to treat disease conditions associated with or caused by herpes viruses. Other objects of the present invention are described in the following description and examples.

In one embodiment, the present invention provides a compound of formula (I): Where: X is , a 5-6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring members, a 5-6 membered heterocycloalkyl group having 1 to 4 ring members independently selected from N, NH, NR ¹⁷ , O or S, or a 5-6 membered heterocyclic group having 1 to 4 ring members independently selected from N, NH, NR ¹⁷ , O or S; Y is a bond, , wherein the * of Y indicates the point of attachment to X and the ** of Y indicates the point of attachment to ^RB ; q is 0 or 1; when q is 1, _LMC is *-((CR ¹¹ R ¹² ) _n O) _m (CR ¹¹ R ¹² ) _p -**, *-C(═O)NR ¹⁵ ((CR ¹¹ R ¹² ) _n O) _m (CR ¹¹ R ¹² ) _p -**, *-(CR ¹¹ R ¹² ) _n NR ¹⁵ ((CR ^{11 R 12} ) _n O) _m (CR ¹¹ R ¹² ) p - _** , *-(CR ¹¹ R ¹² ) _n NR ^{15 )} _m ( _CR ¹¹ R ¹² ) _p -** ^, *-(CR ¹¹ R ¹² ) (CR ¹¹ R ¹² ) _n -**, *-C(=O)NR ¹⁵ (CR ¹¹ R ¹² ) _n -**, *-O(CR ¹¹ R ¹² ) _n -**, or *-NR ¹⁵ (CR ¹¹ R ¹² ) _n -**, wherein the * of L _MC indicates the point of attachment to Z and the ** of L _MC indicates the point of attachment to A; when q is 1, L _MC exists, A is a bond and Z is , wherein the * of Z indicates the point of attachment to L _MC and the ** of Z indicates the point of attachment to L; m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each n is independently selected from 1, 2, 3, 4, 5, 7, 8, 9 and 10; p is 1, 2, 3, 4, 5 or 6; when q is 0, L _MC is absent, and Z is W, and A is R ⁴ ; ^RB is H, C ₁ -C ₆ alkyl, phenyl, pyridyl, thienyl, pyrimidinyl or 5-8 membered cycloalkyl, wherein ^RB is optionally substituted with 1 to 3 R ⁵ groups; R ¹ is selected from H, C _1- C ₃ alkyl and C _1- C ₃ alkyl substituted with 1 to 3 -OH groups; R ² is selected from H, C _1- C ₃ alkyl and C _1- C 3 alkyl substituted with 1 to 3 -OH groups ₃ alkyl; or R ¹ and R ² together with the carbon to which they are attached can form a 3-6 membered cycloalkyl ring; t is 0, 1 or 2; each R ^3, when present, is a substituent on the ring to which -LZ is directly attached, wherein each R ³ is independently selected from halogen, CN, C _1- C ₃ alkoxy, C _1- C ₃ alkyl, C(=O)OR ¹⁰ and C(=O)NR ¹³ R ¹⁴ ; R ⁴ is H, C _1- C ₃ alkyl, C _3- C ₆ cycloalkyl, -(CH ₂ ) ₂ O(CH ₂ ) ₂ Br or C _1- C ₃ alkyl substituted with 1 to 2 groups independently selected from -OH, -C(=O)R ¹⁵ and R ¹⁰ ; each R ⁵ is independently selected from halogen, -CN, hydroxyl, -NR ¹³ R ¹⁴ , C _{3 -} C ₆ cycloalkyl, C _{1 -} C ₃ alkoxy, C _{1 -} C ₃ halogenalkyl and C 1 _- C ₃ alkyl optionally substituted with 1 to 3 R ⁶ groups, wherein when R ^B is substituted with two R ⁵ and each R ⁵ is C _{1 -} C ₃ alkyl optionally substituted with 1 to 3 R ⁶ groups, when directly attached to the same carbon atom, together with the carbon to which the two are directly attached, they can form a 3-5 membered cycloalkyl ring optionally substituted with 1 to 3 R ⁶ groups; each R ⁶ is independently selected from halogen, hydroxy, CN, C _{1 -} C ₃ alkoxy, C _{1 -} C ₃ alkyl and C _{3 -} C ₅ cycloalkyl, or two R wherein the ^6- membered group together with the two directly attached carbon atoms can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as a ring member and optionally substituted by 1 to 2 groups independently selected from pendoxy groups and C _1- C ₃ alkyl groups; L is a C ₁ -C ₄ straight chain or branched chain alkyl linking group, or when W is an optionally substituted ring, L can be a C ₁ -C ₄ straight chain or branched chain alkyl linking group or a single bond; W is H, -OH, -OR ¹⁰ , -C(=O)NR ¹³ R ¹⁴ , -C(=O)OR ¹³ , -NR ¹³ R ¹⁴ , -NR ¹³ C(=O)OR ¹⁰ , -NR ¹³ C(=O)R ¹⁰ , -SO ₂ R ¹⁰ , -SO ₂ NR ¹³ R ¹⁴ , -NR ¹³ SO ₂ R ¹⁰ , -P(=O)(OR ¹³ ) ₂ , -S(=O)R ¹⁰ , -S(=O)(=NR ¹³ )R ¹⁰ , -CR ¹¹ R ¹² C(=O)NR ¹³ R ¹⁴ , -CR ¹¹ R ¹² C(=O)OR ¹³ , -CR ¹¹ R ¹² NR ¹³ R ¹⁴ , -CR ¹¹ R ¹² NR ¹³ C(=O)OR ¹⁰ , -CR ¹¹ R ¹² NR ¹³ C(=O)R ¹⁰ , -CR ¹¹ R ¹² SO ₂ R ¹⁰ , -CR ¹¹ R ¹² SO ₂ NR ¹³ R ¹⁴ , -CR ¹¹ R ¹² NR ¹³ SO ₂ R ¹⁰ , -CR ¹¹ R ¹² P(═O)(OR ¹³ ) ₂ , -CR ¹¹ R ¹² S(═O)R ¹⁰ , -CR ¹¹ R ¹² S(═O)(═NR ¹³ )R ¹⁰ , 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S, 5-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S, or 5 membered heteroaryl having 1 to 4 hetero atoms selected from N, O and S as ring members, which is optionally fused to a phenyl group, wherein the 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-membered heteroaryl of W are each optionally substituted by 1 to 3 groups independently selected from the following groups: C _{1 -} C ₃ alkyl, oxo, halogen, C _{1 -} C ₃ halogenalkyl, -L ² OH, -L ² OR ¹⁰ , -L ² OC(═O)NR ¹³ R ¹⁴ , -L ² SO ₂ R ¹⁰ , -L ² SO ₂ NR ¹⁴ R ¹⁰ , -L ² SO ₂ NR ¹³ R ¹⁴ , -L ² SO ₂ N═CR ¹³ NR ¹³ R ¹⁴ , -L ² SO ₂ NR ¹³ C(═O)R ¹⁰ , -L ² C(═O)NR ¹³ SO ₂ R ¹⁰ , -L ² S(=O)R ¹⁰ , -L ² S(=O) (=NR ¹³ )R ¹⁰ , -L ² NR ¹³ SO ₂ NR ¹³ R ¹⁴ , -L ² NR ¹³ SO ₂ R ¹⁰ , -L ² NR ¹³ R ¹⁴ , -L ² NR ¹³ C(=O)R ¹³ , -L ² NR ¹³ C(=O)OR ¹⁰ , -L ² C(=O)NR ¹³ R ¹⁴ and -L ² C(=O) OR ¹³ ; R ¹⁰ is selected from C _1- C ₅ alkyl, C _1- C , _3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, 4-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S, and 4-6 membered heterocyclo containing 1 to 2 ring members independently selected from N, NH, NR 17 , O or S, wherein each R ¹⁰ is optionally substituted with 1 to 5 groups independently selected from the following: C 1-C 4 alkyl, deuterium, C 1-C 4 halogenoxy, -L 3 OH, -L ³ CN, -L 3 OC(═O)R 14 , -L 3 OR 13 , C _1- C ₄ alkyl, deuterium, C _1- C ₄ halogenoxy, -L 3 OH, -L 3 CN, -L ³ OC(═O)R ¹⁴ , -L 3 OR 13 , C 1-C 4 alkyl, deuterium, C ₁ -C 4 halogenoxy, -L ³ OH, -L ³ CN, -L 3 OC(═O)R 14 , -L ³ OR ¹³ , _{-L 3} halogenalkyl, pendoxy, -L ³ halogen, -L ³ C _1- C ₃ alkoxy, -L ³ OC(=O)NR ¹³ R ¹⁴ , -L ³ SO ₂ R ¹³ , -L ³ SO ₂ NR ¹³ R ¹⁴ , -L ³ SO ₂ NR ¹³ C(=O)R ¹³ , -L ³ C(=O)NR ¹³ SO ₂ R ¹³ , -L ³ S(=O)R ¹³ , -L ³ S(=O)(=NR ¹⁴ )R ¹³ , -L ³ NR ¹³ SO ₂ NR ¹³ R ¹⁴ , -L ³ NR ¹³ SO ₂ R ¹³ , -L ³ NR ¹³ R ¹⁴ , -L ³ NR ¹⁴ C(=O)R ¹³ , -L ^-3- NR ¹⁴ C(=O)OR ¹³ , -L ³ C(=O)NR ¹³ R ¹⁴ , -L ³ C(=O)OR ¹³ , -L ³ -(4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S), -L ³ -(4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S), -L ³ -C _3- C ₅ cycloalkyl and -L ³ -(5-6 membered heteroaryl ring having 1 to 4 hetero atoms including 1 to 4 nitrogen atoms, 0 or 1 oxygen atom and 0 or 1 sulfur atom as ring members), wherein the C _1- C The _4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, C _{3 -} C ₅ cycloalkyl and 5- to 6-membered heteroaryl ring are each optionally further substituted with 1 to 3 groups independently selected from the following: halogen, C _{1 -} C ₃ alkyl, C _{1 -} C ₃ halogenalkyl, -L ⁴ OR ¹³ , -L ⁴ CN and -L ⁴ NR ¹³ R ¹⁴ ; R ¹¹ and R ¹² are each independently selected from H and C _{1 -} C ₄ alkyl; each R ¹³ is independently selected from H, C _{1 -} C ₄ alkyl, 4- to 7-membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, 4- to 7-membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S. , O or S as a ring member, wherein the C _{1 -} C ₄ alkyl, heterocycloalkyl, heterocycloalkyl and C _{3 - C 6 cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C 1 - C 4 alkyl, halogen, -OH, -NR 15 R 16 , -C (= O) OR 15 , C 1 - C 2 alkoxy and C 1 - C 4 alkyl substituted with 1 to 2 hydroxyl groups; R 14 is selected from H, C 1 - C 4 alkyl} ^{and C} _{3 - C 6} cycloalkyl, wherein the C 1 - C ₄ alkyl and C 3 - C 6 cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C 1 - C ₄ alkyl, halogen, -OH, -NR ¹⁵ R 16 , -C (= O) OR 15 , C 1 - C 2 alkoxy and C ₁ - C 4 alkyl substituted with 1 to ₂ hydroxyl groups; R ¹⁴ is selected from H, C _{1 - C} 4 alkyl and C 3 - C 6 cycloalkyl, wherein the C _{1 -} C ₄ alkyl and C _{3 -} C ₆ cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C _{1 -} C R ¹⁵ and R ¹⁶ are each independently selected from _H and C _{1- C 4 alkyl; each R 17 is independently selected from H, C 1-} C ₄ alkyl and C 3 -C 8 cycloalkyl; or R ¹⁷ is C _1- C ₄ alkyl, halogen, -OH, -NR 15 R ¹⁶ , C _1- C ₂ alkoxy and C _{1- C 4 alkyl substituted with 1 to 2 hydroxyl groups; or R 13 and R 14 together with the nitrogen atom to which both are directly attached may form a 4-6 membered ring which optionally contains additional N, O or S as ring members and optionally is substituted with one to three groups selected from C 1- C 2 alkyl, C 1-} ^{C 2 alkoxy, pendoxy and hydroxyl groups; R 15} _and R ¹⁶ are each independently selected from H and C _1- C ₄ alkyl; each R ¹⁷ is independently selected from H, C _1- C ₄ alkyl and C ₃ -C ₈ cycloalkyl; or R ¹⁷ is C _1- C ₄ alkyl, which together with the nitrogen atom to which it is directly attached and the nitrogen atom from the pyrazole ring can form a 5-8 membered ring fused to the pyrazole ring; each of L ² and L ³ and L ⁴ is independently a bond or a straight chain or branched chain C _1- C ₃ alkylene group; and ' indicates a single key or double keys.

Another aspect of the present invention is a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In one embodiment of this aspect, the pharmaceutical composition according to the present invention further comprises a therapeutically effective amount of at least one other antiviral agent.

Another aspect of the present invention relates to a method for treating or preventing hepatitis virus disease and/or infection in humans, which comprises administering to humans an antiviral effective amount of the compound of the present invention, its pharmaceutically acceptable salt or the composition as described above, alone or in combination with at least one other antiviral agent, together or separately.

Another aspect of the present invention relates to a method for treating or preventing herpes virus diseases and/or infections in humans by administering to humans a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, either together or separately.

Another aspect of the present invention is a method for inhibiting the replication of CMV or another herpes virus, which method comprises exposing the virus to an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof under conditions that inhibit viral replication. This method can be implemented in vitro or in vivo.

Another aspect of the present invention is the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing herpes virus diseases and/or infections including CMV in humans.

Another embodiment of the present invention provides a compound as described above or a pharmaceutically acceptable salt thereof as a drug.

Another aspect of the present invention is the use of the pharmaceutical composition as described above for treating CMV infection or other herpes virus in a human having CMV infection or other herpes virus or at risk of having such infection.

Another aspect of the present invention is the use of the pharmaceutical composition as described above for treating CMV disease or other herpes virus infection in a human suffering from CMV disease or other herpes virus infection or at risk of suffering from such disease.

Another aspect of the invention relates to a method for treating a viral disease and/or infection in a human, the method comprising administering to a human an antivirally effective amount of a compound of the invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, together or separately, wherein the viral disease or infection is selected from CMV infection in an immunocompromised patient (e.g., a transplant recipient), congenital CMV, genital herpes, oral herpes (cold sores), herpetic keratitis, neonatal herpes, herpetic encephalitis, varicella (chickenpox), herpes zoster (shingles), infectious mononucleosis, post-transplant lymphoproliferative disease (PTLD), Castelman's disease, and hemophagocytic lymphohistiocytosis.

Another aspect of the present invention relates to a method for treating a disease that can be induced/aggravated/accelerated by herpes virus infection in a human, the method comprising administering to the human an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), chylous diarrhea, and type 1 diabetes.

Another aspect of the present invention relates to a method for treating a disease that can be induced/aggravated/accelerated by herpes virus infection in a human, the method comprising administering to the human an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), chylous diarrhea, and type 1 diabetes.

Another aspect of the present invention is the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a disease that can be induced/aggravated/accelerated by herpes virus infection, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), chylous diarrhea and type 1 diabetes.

Another aspect of the present invention is the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a disease that can be induced/aggravated/accelerated by herpes virus infection, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), chylous diarrhea and type 1 diabetes.

Another aspect of the invention is the use of a pharmaceutical composition as described herein for treating a viral disease and/or infection in a human, wherein the viral disease or infection is selected from CMV infection, congenital CMV, genital herpes, oral herpes (cold sores), herpetic keratitis, neonatal herpes, herpetic encephalitis, varicella (chickenpox), herpes zoster (shingles), infectious mononucleosis, post-transplant lymphoproliferative disease (PTLD), Castleman's disease and hemophagocytic lymphohistiocytosis in an immunocompromised patient (e.g., a transplant recipient).

Another aspect of the present invention is the use of the pharmaceutical composition as described herein for treating a disease that can be induced/aggravated/accelerated by herpes virus infection, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), chylous diarrhea and type 1 diabetes.

Another aspect of the present invention is the use of the pharmaceutical composition as described herein for treating a disease that can be induced/aggravated/accelerated by herpes virus infection, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), chylous diarrhea and type 1 diabetes.

Related applications

This application claims priority to U.S. Provisional Application No. 62/906,664 filed on September 26, 2019, the contents of which are incorporated herein by reference.

Various enumerated embodiments of the present invention are described herein. It should be recognized that features specified in each embodiment may be combined with other specified features to provide other embodiments of the present invention. Definition

For the purpose of interpreting this specification, the following definitions shall apply and terms used in the singular shall also include the plural where appropriate. Unless the context clearly indicates otherwise, the terms used in this specification have the following meanings.

As used herein, the term "alkyl" refers to a fully saturated branched or straight chain hydrocarbon. In certain embodiments, the alkyl group is "C ₁ -C ₂ alkyl", "C ₁ -C ₃ alkyl", "C ₁ -C ₄ alkyl", "C ₁ -C ₅ alkyl", "C ₁ -C ₆ alkyl", "C ₁ -C ₇ alkyl", "C ₁ -C ₈ alkyl", "C ₁ -C ₉ alkyl" or "C ₁ -C ₁₀ alkyl", wherein as used herein, the terms "C ₁ -C ₂ alkyl", "C ₁ -C ₃ alkyl", "C ₁ -C ₄ alkyl", "C ₁ -C ₅ alkyl", "C ₁ -C ₆ alkyl", "C ₁ -C ₇ alkyl", "C ₁ -C ₈ alkyl", "C ₁ -C ₉ alkyl" and "C ₁ -C _" alkyl" refers to an alkyl group containing at least 1 and at most 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, respectively. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

As used herein, the term "alkoxy" refers to -O-alkyl or -alkyl-O-, wherein alkyl is as defined herein. In certain embodiments, the alkoxy group is "C ₁ -C ₂ alkoxy", "C ₁ -C ₃ alkoxy", "C ₁ -C ₄ alkoxy", "C ₁ -C ₅ alkoxy", "C ₁ -C 6 alkoxy", "C ₁ -C ₇ alkoxy", "C ₁ -C ₈ alkoxy", "C _{1 -C 9 alkoxy} " or "C ₁ -C ₁₀ alkoxy", wherein as used herein, the terms "C ₁ -C ₂ alkoxy", "C ₁ -C ₃ alkoxy", "C ₁ -C ₄ alkoxy", "C ₁ -C ₅ alkoxy", "C ₁ -C ₆ alkoxy", "C ₁ -C ₇ alkoxy", "C ₁ -C ₈ alkoxy", "C ₁ -C ₉ alkoxy" and "C ₁ -C ₁₀ alkoxy" refer to -OC _{1 In} some embodiments _, the present invention relates to an alkyl group comprising: _{an alkyl group} , _an alkyl group, _{an alkyl group} , an alkyl group, an alkyl _group , _an alkyl group, _an alkyl group _, an alkyl group, an alkyl group, an _alkyl group, an _alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an _alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, _an alkyl group, an alkyl group, an alkyl _group , an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group, an alkyl group,

As used herein, the term "alkylene" refers to a saturated branched or straight chain divalent hydrocarbon group derived from an alkyl group as defined herein. In certain embodiments, the alkylene group is " _C1 - _C3 alkylene", " _C1 - _C4 alkylene", " _C1 - _C5 alkylene", " _C1 - _C6 alkylene", " _C1 - _C7 alkylene", " _C1 - _C8 alkylene", " _C1 - _C9 alkylene" or "C1- _C10 alkylene", wherein as used herein, the terms " _C1 - _C3 alkylene", " _C1 -C4 alkylene", " _C1 -C5 alkylene", " _C1 - _C6 alkylene", " _C1 - _C7 alkylene" and " _C1 - _C8 alkylene" refer to alkylene groups containing at least 1 and at _most 3, ₄ , 5, ₆ , 7, 8, 9 or 10 carbon atoms, respectively. As used herein, non-limiting examples of alkylene groups include methylene, ethylene, n-propylene, isopropylene, n-butylene, isobutylene, sec-butylene, t-butylene, n-pentylene, isopentylene, hexylene, heptylene, octylene, nonylene, decylene, and the like.

In certain embodiments, the alkylene group is a "C ₁ -C ₂ alkylene group", which refers to an alkylene group containing at least 1 and at most 2 carbon atoms.

As used herein, the term "C ₃ -C ₈ cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having 3 to 8 carbon atoms as ring members. Non-limiting examples of such "C ₃ -C ₈ cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, the term "C ₃ -C ₆ cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having 3 to 6 carbon atoms as ring members. Non-limiting examples of such "C ₃ -C ₆ cycloalkyl" include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

As used herein, the term "C ₅ -C ₈ cycloalkyl" refers to a fully saturated monocyclic hydrocarbon ring system having 5 to 8 carbon atoms as ring members. Non-limiting examples of such "C ₅ -C ₈ cycloalkyl" include cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As used herein, the term "haloalkyl" refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group is replaced by a halogen group as defined herein. The halogen alkyl group may be a monohalogen alkyl group, a dihalogen alkyl group, a trihalogen alkyl group, or a polyhalogen alkyl group, including a perhalogen alkyl group. A monohalogen alkyl group may have one iodo, bromo, chloro, or fluoro group in the alkyl group. A dihalogen alkyl group may have two and a polyhalogen alkyl group may have two or more of the same halogen atoms or a combination of different halogen groups in the alkyl group. Typically, a polyhalogen alkyl group contains up to 6, or 4, or 3, or 2 halogen groups. Non-limiting examples of halogenalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. Fully halogenalkyl refers to an alkyl group in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethyl. Unless otherwise specified, representative haloalkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl groups in which at least one hydrogen is substituted with a _halogen , such as where the halogen is _fluorine : _CF3CF2- , ( _CF3 ) _{2CH- , CH3 - CF2- , CF3CF2- , CF3} , _CF2H- , _CF3CF2CH ( _CF3 )-, or _{CF3CF2CF2CF2-} .

As used herein, the term "C ₁ -C ₃ haloalkyl" refers to the corresponding "C ₁ -C ₃ alkyl" as defined herein, wherein at least one of the hydrogen atoms of the "C ₁ -C ₃ alkyl" is replaced by a halogen atom. The C ₁ -C ₃ haloalkyl may be a mono-C ₁ -C ₃ haloalkyl, wherein such a C ₁ -C ₃ haloalkyl has one iodo group, one bromo group, one chloro group or one fluoro group. In addition, the C ₁ -C ₃ haloalkyl may be a di-C ₁ -C ₃ haloalkyl, wherein such a C ₁ -C ₃ haloalkyl may have two halogen atoms independently selected from iodo groups, bromo groups, chloro groups or fluoro groups. In addition, the C ₁ -C ₃ haloalkyl group may be a poly-C ₁ -C ₃ haloalkyl group, wherein such a C ₁ -C ₃ haloalkyl group may have two or more identical halogen atoms or a combination of two or more different halogen atoms. Such a poly-C ₁ -C ₃ haloalkyl group may be a perhalogen C ₁ -C ₃ haloalkyl group, wherein all hydrogen atoms corresponding to the C ₁ -C ₃ alkyl group are replaced by halogen atoms and the halogen atoms may be the same halogen atom or a combination of different halogen atoms. Non-limiting examples of "C ₁ -C ₃ haloalkyl group" include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, fluoroethyl, difluoroethyl, trifluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

As used herein, the term "haloalkoxy" refers to the group -O-alkyl, wherein "alkyl" is as defined herein and wherein at least one of the hydrogen atoms of the alkyl is replaced by a halogen as defined herein for "haloalkyl". The halogen alkoxy group may be a monohalogen alkoxy group, a dihalogen alkoxy group, a trihalogen alkoxy group or a polyhalogen alkoxy group, including a perhalogen alkoxy group. A monohalogen alkoxy group may have one iodo, bromo, chloro or fluoro group in the alkyl group. A dihalogen alkoxy group may have two and a polyhalogen alkoxy group may have two or more of the same halogen atoms or a combination of different halogen groups in the alkyl group. Typically, a polyhalogen alkoxy group contains up to 6, or 4, or 3, or 2 halogen groups. Non-limiting examples of halogen alkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, difluoroethoxy, dichloroethoxy, and dichloropropoxy. Perhalogen alkoxy refers to an alkoxy group in which all hydrogen atoms are replaced by halogen atoms, such as trifluoromethoxy. Unless otherwise specified, representative halogen alkoxy groups include methoxy and ethoxy groups substituted with monofluoro, difluoro, and trifluoro, such as _-OCF3 , _-OCHF2 , _{-OCH2F , -OCH2CHF2 , and -OCH2CF3} .

As used herein, the term "C ₁ -C ₄ haloalkoxy" refers to a group -OC ₁ -C ₄ alkyl, wherein "alkyl" is as defined herein and wherein at least one of the hydrogen atoms of the "C ₁ -C ₄ alkyl" is replaced by a halogen atom as defined herein for "haloalkyl". The C ₁ -C ₄ haloalkoxy group may be a mono-C ₁ -C ₄ haloalkoxy group, wherein such a C ₁ -C ₄ haloalkoxy group has one iodo group, one bromo group, one chloro group or one fluoro group. In addition, the C ₁ -C ₄ haloalkoxy group may be a di-C ₁ -C ₄ haloalkoxy group, wherein such a C ₁ -C ₄ haloalkoxy group may have two halogen atoms independently selected from iodo group, bromo group, chloro group or fluoro group. In addition, the C ₁ -C ₄ halogen alkoxy group may be a poly-C ₁ -C ₄ halogen alkoxy group, wherein such a C ₁ -C ₄ halogen alkoxy group may have two or more identical halogen atoms or a combination of two or more different halogen atoms. Such a poly-C ₁ -C ₄ halogen alkoxy group may be a perhalogen C ₁ -C ₄ halogen alkoxy group, wherein all hydrogen atoms corresponding to the C ₁ -C ₄ alkoxy group are replaced by halogen atoms and the halogen atoms may be the same halogen atom or a combination of different halogen atoms. Non-limiting examples of “C ₁ -C ₄ halogenalkoxy” include fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, pentafluoroethoxy, heptafluoropropoxy, difluorochloromethoxy, dichlorofluoromethoxy, fluoroethoxy, difluoroethoxy, trifluoroethoxy, difluoropropoxy, dichloroethoxy and dichloropropoxy.

As used herein, the term "halogen" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).

As used herein, the term "heteroaryl" refers to i) a 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 5-6 membered monocyclic ring system having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members, but the heteroaryl ring usually contains at most one divalent O or S in the ring, ii) a 5-6 membered heteroaryl having 1 to 3 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 5-6 membered monocyclic ring system having 1 to 3 heteroatoms independently selected from heteroatoms N, O and S as ring members, iii) 5-6 membered heteroaryl having 1 to 2 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 5-6 membered monocyclic ring system having 1 to 2 heteroatoms independently selected from heteroatoms N, O and S as ring members, iv) 5 membered heteroaryl having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 5 membered monocyclic ring system having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members, v) 6-membered heteroaryl having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 6-membered monocyclic ring system having 1 to 4 heteroatoms independently selected from heteroatoms N, O and S as ring members, vi) 5-6-membered heteroaryl having 1 to 4 nitrogen atoms as ring members, which refers to an aromatic 5-6-membered monocyclic ring system having 1 to 4 nitrogen atoms as ring members, vii) 9-10-membered bicyclic heteroaryl having 1 to 2 heteroatoms independently selected from heteroatoms N, O and S as ring members, which refers to an aromatic 5-6-membered monocyclic ring system having 1 to 4 nitrogen atoms as ring members, as a heteroatom selected from N, O and S as a heteroatom, and viii) a 9-10 membered bicyclic heteroaryl group having 1 to 3 heteroatoms independently selected from N, O and S as a heteroatom, which refers to an aromatic 9-10 membered bicyclic fused ring system having 1 to 3 heteroatoms independently selected from N, O and S as a heteroatom.

As used herein, non-limiting examples of heteroaryl groups include benzofuranyl, benzo[c]thienyl, benzothienyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, oxazolyl, furazanyl, furanyl, imidazolyl, indolyl, indolizinyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, isothiazolyl, oxazolyl, oxaindolyl, oxadiazolyl, pyrazolyl, pyrrolyl, phthalinyl, pyridinyl, oxadiazolyl, pyrimidinyl, quinoxalinyl, quinolinyl, quinazolinyl, tetrazolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, and triazolyl.

As used herein, the term “heteroatoms” or “hetero atoms” refers to nitrogen (N), oxygen (O) or sulfur (S) atoms.

As used herein, the term "heterocycloalkyl" refers to a cycloalkyl as defined herein wherein one to two carbon atoms in the ring structure are replaced by one to two groups independently selected from N, NH, NR ¹⁷ , O or -S-, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl. The heterocycloalkyl group may be, in particular, i) a 4- to 6-membered heterocycloalkyl group containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or -S-, which refers to a 4- to 6-ring membered heterocycloalkyl group having a fully saturated monocyclic hydrocarbon ring structure of 4 to 6 ring members, wherein one to two of the ring members are independently selected from N, NH, NR ¹⁷ , O or -S-, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, ii) a 4- to 6-membered heterocycloalkyl group containing one to two ring members independently selected from N, NH, NR ¹⁷ , O or -S-, which refers to a 5-6 ring member heterocycloalkyl group having a fully saturated monocyclic hydrocarbon ring structure with 5-6 ring members, wherein one to two of the ring members are independently selected from N, NH, NR ¹⁷ , O or -S-, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, and iii) contains one to two independently selected from N, NH, NR ¹⁷ , O or -S- as ring members, which refers to an 8- to 10-membered heterocycloalkyl group having a fully saturated fused bicyclic ring structure of 8 to 10 ring members, wherein one to two of the ring members are independently selected from N, NH, NR ¹⁷ , O or -S-, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl.

As used herein, non-limiting examples of heterocycloalkyl groups include azetidinyl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl, oxacyclobutanyl, oxacyclobutanyl, oxacyclobutanyl-2-yl, oxacyclobutanyl-3-yl, oxacyclobutanyl-4-yl, thiacyclobutanyl, thiacyclobutanyl-5-yl, thiacyclobutanyl-6-yl, thiacyclobutanyl-7-yl, thiacyclobutanyl-8-yl, thiacyclobutanyl-9-yl, thiacyclobutanyl-10-yl, thiacyclobutanyl-20-yl, thiacyclobutanyl-30-yl, thiacyclobutanyl-40-yl, thiacyclobutanyl-50-yl, thiacyclobutanyl-60-yl, thiacyclobutanyl-70-yl, thiacyclobutanyl-80-yl, thiacyclobutanyl-90-yl, thiacyclobutanyl-100-yl, thiacyclobutanyl-200-yl, thiacyclobutanyl-300-yl, 2-yl, thiacyclobutan-3-yl, thiacyclobutan-4-yl, pyrrolidinyl, pyrrolidin-1-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, pyrrolidin-4-yl, pyrrolidin-5-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrofuran-4-yl, tetrahydrofuran-5-yl, tetrahydrothienyl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, tetrahydrothien-4-yl, tetrahydrothien-5-yl, piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, piperidin-5-yl, piperidin-6-yl, tetrahydropyranyl, tetrahydropyran-2-yl yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl, tetrahydropyran-5-yl, tetrahydropyran-6-yl, tetrahydrothiopyranyl, tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl, tetrahydrothiopyran-4-yl, tetrahydrothiopyran-5-yl, tetrahydrothiopyran-6-yl, piperidine, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl, piperidine-5-yl, piperidine-6-yl, morpholinyl, morpholin-2-yl, morpholin-3-yl, morpholin-4-yl, morpholin-5-yl, morpholin-6-yl, thiomorpholinyl, thiomorpholin-2-yl, thiomorpholin-3-yl, thiomorpholin-4-yl, thiomorpholin-6-yl -5-yl, thiophene-6-yl, oxathiolanyl, oxathiolanyl-2-yl, oxathiolanyl-3-yl, oxathiolanyl-5-yl, oxathiolanyl-6-yl, dithianyl, dithiane-2-yl, dithiane-3-yl, dithiane-5-yl, dithiane-6-yl, dioxathiolanyl cyclopentanyl, dioxacyclopentan-2-yl, dioxacyclopentan-4-yl, dioxacyclopentan-5-yl, thiocyclohexanyl, thiocyclohexan-2-yl, thiocyclohexan-3-yl, thiocyclohexan-4-yl, thiocyclohexan-5-yl, dithiocyclopentanyl, dithiocyclopentan-2-yl, dithiocyclopentan-3-yl, dithiocyclopentan-4-yl, dithiocyclopent ...3-yl, dithiocyclopentan-4-yl, dithiocyclopentan-5-yl, dithiocyclopentanyl, dithiocyclopentan-2-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclopentan-3-yl, dithiocyclo yl, dithiocyclopentan-4-yl, dithiocyclopentan-5-yl, pyrazolidinyl, pyrazolidin-1-yl, pyrazolidin-2-yl, pyrazolidin-3-yl, pyrazolidin-4-yl, pyrazolidin-5-yl, 2-azabicyclo[4.2.0]octanyl, octahydro-1H-cyclopenta[b]pyridine and decahydroquinoline.

The term "hydroxy" or "hydroxyl" refers to the group -OH.

As used herein, the term "oxo" refers to a "=0" group.

As used herein, the term "heterocyclic group" refers to a 4- to 14-membered saturated or partially saturated hydrocarbon ring structure having 1 to 7, 1 to 5, 1 to 3, or 1 to 2 ring members independently selected from N, NH, NR ³⁶ , O, or S, wherein R ³⁶ is C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl. The term "heterocyclic group" includes a monocyclic group, a bicyclic group, a fused cyclic group, a spirocyclic group, and a bridged cyclic group. The heterocyclic group may be attached to another group at a nitrogen or carbon atom. The heterocyclic group may be, in particular, i) a 4-6 membered heterocyclic group containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, ii) a 4-7 membered heterocyclic group containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, iii) a 5-6 membered heterocyclic group containing 1 to 4 ring members independently selected from N, NH, NR ¹⁷ , O or S, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, iv) a 5-6 membered heterocyclic group containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, v) a 8-10 membered fused bicyclic heterocyclic group containing 1 to 3 ring members independently selected from N, NH, NR ¹⁷ , O or S, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl, and vi) a 8-10 membered fused tricyclic heterocyclic group containing 1 to 4 ring members independently selected from N, NH, NR ¹⁷ , O or S, wherein R ¹⁷ is H, C ₁ -C ₆ alkyl or C ₃ -C ₈ cycloalkyl.

As used herein, non-limiting examples of heterocycloalkyl groups include dihydrobenzofuranyl, dihydrobenzo[c]thienyl, dihydrobenzothienyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzimidazolyl, dihydroxanthinyl, dihydrofurazanyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl, dihydroindolizinyl, dihydroindazolyl, dihydroisindolyl, dihydroisoquinolinyl, dihydroisoxazolyl, dihydroisothiazolyl, dihydro oxazolyl, dihydroindolyl, dihydrodiazolyl, dihydropyrazolyl, dihydropyrrolyl, dihydrophthalidinyl, dihydropyridinyl, dihydrophthalidinyl, dihydropyridinyl, dihydropyridinyl, dihydropyrimidinyl, dihydroquinoxaline, dihydroquinolinyl, dihydroquinazolinyl, dihydrotetrazolyl, dihydrothiazolyl, dihydrothiadiazolyl, dihydrothienyl, dihydrotriazolyl, dihydrotriazolyl, tetrahydrobenzofuranyl, tetrahydrobenzo[c]thienyl, tetrahydrobenzothienyl, tetrahydrobenzoxazolyl, tetrahydrobenzothiazolyl, tetrahydrobenzimidazolyl, tetrahydrooxalinyl, tetrahydroindolyl, tetrahydroindole, tetrahydroindazolyl, tetrahydroisoindolyl, tetrahydroisoquinolinyl, tetrahydroindolyl, tetrahydrophthalindolyl, tetrahydropyridinyl, tetrahydroxanthinyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydroquinoxalinyl, tetrahydroquinolinyl, tetrahydroquinazolinyl, tetrahydrotriazolyl, hexahydrobenzofuranyl, hexahydrobenzo[c]thienyl , hexahydrobenzothiophenyl, hexahydrobenzoxazolyl, hexahydrobenzothiazolyl, hexahydrobenzimidazolyl, hexahydrooxolinyl, hexahydroindolyl, hexahydroindolizyl, hexahydroindazolyl, hexahydroisoindolyl, hexahydroisoquinolinyl, hexahydroindolyl, hexahydrophthalimidazolyl, hexahydrophthalimidazolyl, hexahydroquinoxalinyl, hexahydroquinolinyl, hexahydroquinazolinyl, octahydrooxolinyl, octahydroisoquinolinyl, octahydrophthalimidazolyl, octahydroquinoxalinyl, octahydroquinazolinyl and octahydroquinazolinyl.

As used herein, the term "subject" refers to an animal. In some aspects, the animal is a mammal. Subject also refers to, for example, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In some embodiments, the subject is a human. As used herein, "patient" refers to a human subject.

As used herein, the term "linking group" refers to a divalent chemical moiety that is capable of covalently linking two separate chemical moieties together.

As used herein, the term "inhibition" or "inhibiting" refers to the reduction or inhibition of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

The term "optical isomer" or "stereoisomer" refers to any of the various stereoisomeric configurations that may exist for a given compound of the present invention, and includes geometric isomers. It is understood that substituents may be attached at the chiral center of a carbon atom. The term "chiral" refers to the property of a molecule that is non-superimposable with a mirror image partner, while the term "diachiral" refers to a molecule that is superimposable with a mirror image partner. Therefore, the present invention includes enantiomers, diastereomers, or racemates of a compound. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term is used to refer to a racemic mixture when appropriate. "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is assigned according to the Cahn-lngold-Prelog R-S system. When a compound is pure enantiomers, the stereochemistry at each chiral carbon can be assigned R or S. Resolved compounds of unknown absolute configuration can be named (+) or (-) depending on the direction (right-handed or left-handed) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more centers or axes of asymmetry and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

As used herein, the term "treating" or "treatment" of any disease or disorder refers in one embodiment to ameliorating the disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof). In another embodiment, "treating" or "treatment" refers to alleviating or improving at least one physiological parameter, including physiological parameters that may not be discernible to the patient. In yet another embodiment, "treating" or "treatment" refers to regulating the disease or disorder physically (e.g., stabilization of identifiable symptoms), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to preventing or delaying the onset or development or progression of a disease or condition.

The compound names provided herein were obtained using ChemDraw Ultra version 12.0 (CambridgeSoft®) or JChem version 5.3.1 (ChemAxon).

Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (such as "such as") provided herein is intended only to better illustrate the present invention and does not limit the scope of the present invention otherwise claimed.

"Optionally substituted" means that the mentioned group may be substituted at one or more positions with any one or any combination of the groups listed thereafter. It will be understood that the number, position, and selection of substituents encompass only those substitutions that a skilled chemist would expect to be reasonably stable; thus, a "pendooxy" would not be a substituent on, for example, an aryl or heteroaryl ring, and a single carbon atom would not have three hydroxyl or amino substituents.

A group may be substituted at the same position that it is attached to the rest of the defined molecule. For example, a group may be substituted with a cyclopropyl group, and the cyclopropyl group may in turn be substituted with another group at the same carbon that it is attached to the rest of the molecule.

Unless otherwise specified, the terms “compounds of the present invention,” “compounds of the invention,” or “compounds provided herein” refer to compounds of Formula (A)-5D, (IA), (IIb), (IIId), (IVa)-5D, (IVc), (IVd), (Va)-5D, (Vc), (VI), (VII), and (VIII), and pharmaceutically acceptable salts, stereoisomers (including diastereomers and enantiomers), rotamers, tautomers, and isotopically labeled compounds (including deuterium substitution), as well as intrinsically formed moieties.

As used herein, the terms "a", "an", "the" and similar terms used in the context of the present invention (especially in the context of the claims) should be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.

Unless otherwise indicated herein or otherwise clearly contradicted by context, all methods described herein may be performed in any suitable order. The use of any and all examples or exemplary language (e.g., "such as") provided herein is intended only to better illustrate the present invention and does not limit the scope of the present invention otherwise claimed. Compounds of the present invention

The present invention provides a compound having a structure of formula (I), or a pharmaceutically acceptable salt thereof: Where: X is , a 5-6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring members, a 5-6 membered heterocycloalkyl group having 1 to 4 ring members independently selected from N, NH, NR ¹⁷ , O or S, or a 5-6 membered heterocyclic group having 1 to 4 ring members independently selected from N, NH, NR ¹⁷ , O or S; Y is a bond, , wherein the * of Y indicates the point of attachment to X and the ** of Y indicates the point of attachment to ^RB ; q is 0 or 1; when q is 1, _LMC is *-((CR ¹¹ R ¹² ) _n O) _m (CR ¹¹ R ¹² ) _p -**, *-C(═O)NR ¹⁵ ((CR ¹¹ R ¹² ) _n O) _m (CR ¹¹ R ¹² ) _p -**, *-(CR ¹¹ R ¹² ) _n NR ¹⁵ ((CR ¹¹ R ¹² ) _n O) _m (CR ¹¹ R ¹² ) _p -**, ^* -(CR ¹¹ R ¹² ) _n NR ¹⁵ ) _m (CR ¹¹ R ¹² _{) p} -** ^, *-(CR ¹¹ R ¹² ) C(═O)NR ¹⁵ (CR ¹¹ R ¹² ) _n -**, *-C(=O)NR ¹⁵ (CR ¹¹ R ¹² ) _n -**, *-O(CR ¹¹ R ¹² ) _n -**, or *-NR ¹⁵ (CR ¹¹ R ¹² ) _n -**, wherein the * of L _MC indicates the point of attachment to Z and the ** of L _MC indicates the point of attachment to A; when q is 1, L _MC exists, A is a bond and Z is , wherein the * of Z indicates the point of attachment to L _MC and the ** of Z indicates the point of attachment to L; m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each n is independently selected from 1, 2, 3, 4, 5, 7, 8, 9 and 10; p is 1, 2, 3, 4, 5 or 6; when q is 0, L _MC is absent, and Z is W, and A is R ⁴ ; ^RB is H, C ₁ -C ₆ alkyl, phenyl, pyridyl, thienyl, pyrimidinyl or 5-8 membered cycloalkyl, wherein ^RB is optionally substituted with 1 to 3 R ⁵ groups; R ¹ is selected from H, C _1- C ₃ alkyl and C _1- C ₃ alkyl substituted with 1 to 3 -OH groups; R ² is selected from H, C _1- C ₃ alkyl and C _1- C 3 alkyl substituted with 1 to 3 -OH groups ₃ alkyl; or R ¹ and R ² together with the carbon to which they are attached can form a 3-6 membered cycloalkyl ring; t is 0, 1 or 2; each R ^3, when present, is a substituent on the ring to which -LZ is directly attached, wherein each R ³ is independently selected from halogen, CN, C _1- C ₃ alkoxy, C _1- C ₃ alkyl, C(=O)OR ¹⁰ and C(=O)NR ¹³ R ¹⁴ ; R ⁴ is H, C _1- C ₃ alkyl, C _3- C ₆ cycloalkyl, -(CH ₂ ) ₂ O(CH ₂ ) ₂ Br or C _1- C ₃ alkyl substituted with 1 to 2 groups independently selected from -OH, -C(=O)R ¹⁵ and R ¹⁰ ; each R ⁵ is independently selected from halogen, -CN, hydroxyl, -NR ¹³ R ¹⁴ , C _{3 -} C ₆ cycloalkyl, C _{1 -} C ₃ alkoxy, C _{1 -} C ₃ halogenalkyl and C 1 _- C ₃ alkyl optionally substituted with 1 to 3 R ⁶ groups, wherein when R ^B is substituted with two R ⁵ and each R ⁵ is C _{1 -} C ₃ alkyl optionally substituted with 1 to 3 R ⁶ groups, when directly attached to the same carbon atom, together with the carbon to which the two are directly attached, they can form a 3-5 membered cycloalkyl ring optionally substituted with 1 to 3 R ⁶ groups; each R ⁶ is independently selected from halogen, hydroxy, CN, C _{1 -} C ₃ alkoxy, C _{1 -} C ₃ alkyl and C _{3 -} C ₅ cycloalkyl, or two R The ^6- membered group together with the two directly attached carbon atoms can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as a ring member and optionally substituted by 1 to 2 groups independently selected from pendoxy groups and C _1- C ₃ alkyl groups; L is a C ₁ -C ₄ straight chain or branched chain alkyl linking group, or when W is an optionally substituted ring, L can be a C ₁ -C ₄ straight chain or branched chain alkyl linking group or a single bond; W is H, -OH, -OR ¹⁰ , -C(=O)NR ¹³ R ¹⁴ , -C(=O)OR ¹³ , -NR ¹³ R ¹⁴ , -NR ¹³ C(=O)OR ¹⁰ , -NR ¹³ C(=O)R ¹⁰ , -SO ₂ R ¹⁰ , -SO ₂ NR ¹³ R ¹⁴ , -NR ¹³ SO ₂ R ¹⁰ , -P(=O)(OR ¹³ ) ₂ , -S(=O)R ¹⁰ , -S(=O)(=NR ¹³ )R ¹⁰ , -CR ¹¹ R ¹² C(=O)NR ¹³ R ¹⁴ , -CR ¹¹ R ¹² C(=O)OR ¹³ , -CR ¹¹ R ¹² NR ¹³ R ¹⁴ , -CR ¹¹ R ¹² NR ¹³ C(=O)OR ¹⁰ , -CR ¹¹ R ¹² NR ¹³ C(=O)R ¹⁰ , -CR ¹¹ R ¹² SO ₂ R ¹⁰ , -CR ¹¹ R ¹² SO ₂ NR ¹³ R ¹⁴ , -CR ¹¹ R ¹² NR ¹³ SO ₂ R ¹⁰ , -CR ¹¹ R ¹² P(=O)(OR ¹³ ) ₂ , -CR ¹¹ R ¹² S(=O)R ¹⁰ , -CR ¹¹ R ¹² S(=O)(=NR ¹³ )R ¹⁰ , 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S, 5-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S, or 5 membered heteroaryl having 1 to 4 hetero atoms selected from N, O and S as ring members, which is optionally fused to a phenyl group, wherein the 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkyl and 5-membered heteroaryl of W are each optionally substituted by 1 to 3 groups independently selected from the following groups: C _{1 -} C ₃ alkyl, oxo, halogen, C _{1 -} C ₃ halogenalkyl, -L ² OH, -L ² OR ¹⁰ , -L ² OC(═O)NR ¹³ R ¹⁴ , -L ² SO ₂ R ¹⁰ , -L ² SO ₂ NR ¹⁴ R ¹⁰ , -L ² SO ₂ NR ¹³ R ¹⁴ , -L ² SO ₂ N═CR ¹³ NR ¹³ R ¹⁴ , -L ² SO ₂ NR ¹³ C(═O)R ¹⁰ , -L ² C(═O)NR ¹³ SO ₂ R ¹⁰ , -L ² S(=O)R ¹⁰ , -L ² S(=O) (=NR ¹³ )R ¹⁰ , -L ² NR ¹³ SO ₂ NR ¹³ R ¹⁴ , -L ² NR ¹³ SO ₂ R ¹⁰ , -L ² NR ¹³ R ¹⁴ , -L ² NR ¹³ C(=O)R ¹³ , -L ² NR ¹³ C(=O)OR ¹⁰ , -L ² C(=O)NR ¹³ R ¹⁴ and -L ² C(=O)OR ¹³ ; R ¹⁰ is selected from C _1- C ₅ alkyl, C _1- C _1-3 haloalkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, 4-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S, and 4-6 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR 17 , O or S, wherein each R ¹⁰ is optionally substituted with 1 to 5 groups independently selected from the following: C 1-C 4 alkyl, deuterium, C 1-C 4 haloalkoxy, -L 3 OH, -L ³ CN, -L 3 OC(═O)R 14 , -L ³ OR 13 , C _1- C ₄ alkyl, deuterium, C _1- C 4 haloalkoxy, -L ³ OH, -L ³ CN, -L ³ OC(═O)R ¹⁴ , -L 3 OR ¹³ , C 1-C 4 alkyl, deuterium, C _1- C ₄ halogen _{-L 2} halogenalkyl, pendoxy, -L ³ halogen, -L ³ C _1- C ₃ alkoxy, -L ³ OC(=O)NR ¹³ R ¹⁴ , -L ³ SO ₂ R ¹³ , -L ³ SO ₂ NR ¹³ R ¹⁴ , -L ³ SO ₂ NR ¹³ C(=O)R ¹³ , -L ³ C(=O)NR ¹³ SO ₂ R ¹³ , -L ³ S(=O)R ¹³ , -L ³ S(=O)(=NR ¹⁴ )R ¹³ , -L ³ NR ¹³ SO ₂ NR ¹³ R ¹⁴ , -L ³ NR ¹³ SO ₂ R ¹³ , -L ³ NR ¹³ R ¹⁴ , -L ³ NR ¹⁴ C(=O)R ¹³ , -L -L ³ -( ^{4-7 membered heterocycloalkyl} containing 1 to 2 ring members independently selected from N, NH, NR ^{17 ,} O or S), -L ³ -( ^4-7 membered heterocycloalkyl containing 1 to ² ring members independently selected from N, NH, NR ¹⁷ , O or S)), -L ³ -C ₃ -C ₅ cycloalkyl and -L ³ -(5-6 membered heteroaryl ring having 1 to ⁴ hetero atoms including 1 to 4 nitrogen ^atoms , 0 or 1 oxygen atom and 0 or 1 sulfur atom as ring members), wherein the C ¹ _- C The _4- to 7-membered heterocycloalkyl, 4- to 7-membered heterocycloalkyl, C _{3 -} C ₅ cycloalkyl and 5- to 6-membered heteroaryl ring are each optionally further substituted with 1 to 3 groups independently selected from the following: halogen, C _{1 -} C ₃ alkyl, C _{1 -} C ₃ halogenalkyl, -L ⁴ OR ¹³ , -L ⁴ CN and -L ⁴ NR ¹³ R ¹⁴ ; R ¹¹ and R ¹² are each independently selected from H and C _{1 -} C ₄ alkyl; each R ¹³ is independently selected from H, C _{1 -} C ₄ alkyl, 4- to 7-membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, 4- to 7-membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S. , O or S as a ring member, wherein the C _{1 -} C ₄ alkyl, heterocycloalkyl, heterocycloalkyl and C _{3 - C 6 cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C 1 - C 4 alkyl, halogen, -OH, -NR 15 R 16 , -C (= O) OR 15 , C 1 - C 2 alkoxy and C 1 - C 4 alkyl substituted with 1 to 2 hydroxyl groups; R 14 is selected from H, C 1 - C 4 alkyl} ^{and C} _{3 - C 6} cycloalkyl, wherein the C 1 - C ₄ alkyl and C 3 - C 6 cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C 1 - C ₄ alkyl, halogen, -OH, -NR ¹⁵ R 16 , -C (= O) OR 15 , C 1 - C 2 alkoxy and C ₁ - C 4 alkyl substituted with 1 to ₂ hydroxyl groups; R ¹⁴ is selected from H, C _{1 - C} 4 alkyl and C 3 - C 6 cycloalkyl, wherein the C _{1 -} C ₄ alkyl and C _{3 -} C ₆ cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C _{1 -} C R ¹⁵ and _R ¹⁶ are each independently selected from H and C _1- C ₄ ^alkyl ; each of _{L 2 ,} L ^{3 and} L ⁴ is ^{independently} a bond or a straight chain or ^branched chain ^C _{1- C 3 alkylene group ; and} ' indicates a single key or double keys.

Various embodiments of the compounds of the present invention are described herein. It should be recognized that the features specified in each embodiment can be combined with other specified features to provide other embodiments. The following examples represent the compounds of formula (I) of the present invention:Embodiment 1. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is.Embodiment 2. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is.Embodiment 3. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is.Embodiment 4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is.Embodiment 5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is a 5-6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring members.Embodiment 6. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is a compound containing 1 to 4 independently selected from N, NH, NR¹⁷ , O or S as a ring member of a 5-6 membered heterocycloalkyl group.Embodiment 7. A compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is a compound containing 1 to 4 independently selected from N, NH, NR¹⁷ , O or S as a ring member of a 5-6 member heterocyclic group.Embodiment 8. A compound of formula (I), or a compound of any one of Examples 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is.Embodiment 9. A compound of formula (I), or a compound of any one of Examples 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is, where * in Y indicates the point of attachment to X and ** in Y indicates the point of attachment to R^B Attachment point.Embodiment 10. A compound of formula (I), or a compound of any one of Examples 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is -O-.Embodiment 11. A compound of formula (I), or a compound of any one of Examples 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is, where * in Y indicates the point of attachment to X and ** in Y indicates the point of attachment to R^B Attachment point.Embodiment 12. A compound of formula (I), or a compound of any one of Examples 1 to 7, or a pharmaceutically acceptable salt thereof, wherein Y is a bond.Embodiment 13. A compound of formula (I), or a compound of any one of Examples 1 to 12, or a pharmaceutically acceptable salt thereof, wherein q is 1, L_MC Exists and A is a key.Embodiment 14. A compound of formula (I), or a compound of any one of Examples 1 to 13, or a pharmaceutically acceptable salt thereof, wherein q is 1, A is a bond and L_MC *-((CR¹¹ R¹² )_n O)_m (CR¹¹ R¹² )_p -**、*-C(=O)NR¹⁵ ((CR¹¹ R¹² )_n O)_m (CR¹¹ R¹² )_p -**or*-(CR¹¹ R¹² )_n NR¹⁵ ((CR¹¹ R¹² )_n O)_m (CR¹¹ R¹² )_p -**, where L_MC * indicates the attachment point with Z and L_MC ** indicates the attachment point with A.Embodiment 15. A compound of formula (I), or a compound of any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, wherein q is 1, A is a bond and L_MC for, where L_MC * indicates the attachment point with Z and L_MC ** indicates the attachment point with A.Embodiment 16. A compound of formula (I), or a compound of any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, wherein q is 1, A is a bond and L_MC for, where L_MC * indicates the attachment point with Z and L_MC ** indicates the attachment point with A.Embodiment 17. A compound of formula (I), or a compound of any one of Examples 1 to 14, or a pharmaceutically acceptable salt thereof, wherein q is 1, A is a bond and L_MC for, where L_MC * indicates the attachment point with Z and L_MC ** indicates the attachment point with A.Embodiment 18. A compound of formula (I), or a compound of any one of Examples 1 to 17, or a pharmaceutically acceptable salt thereof, wherein q is 1 and Z is, where the * in Z indicates the same_MC 's attachment point and the ** on Z indicates the attachment point with L.Embodiment 19. A compound of formula (I), or a compound of any one of Examples 1 to 17, or a pharmaceutically acceptable salt thereof, wherein q is 1 and Z is, where the * in Z indicates the same_MC 's attachment point and the ** on Z indicates the attachment point with L.Embodiment 20. A compound of formula (I), or a compound of any one of Examples 1 to 12, or a pharmaceutically acceptable salt thereof, wherein q is 0, L_MC Does not exist and Z is W.Embodiment twenty one. A compound of formula (I) having a structure of formula (II), or a pharmaceutically acceptable salt thereof,, W, L, t, R¹ 、R² 、R³ 、R⁴ and R^B As defined for formula (I).Embodiment twenty two. A compound of formula (II) according to any one of Examples 1 to 21, or a pharmaceutically acceptable salt thereof, wherein: R^B is phenyl, pyridyl, thienyl, pyrimidinyl or 5-8 membered cycloalkyl, where R^B 1 to 3 Rs depending on the situation⁵ Group substitution; R¹ Selected from H, C_1- C₃ Alkyl and C substituted with 1 to 3 -OH groups_1- C₃ Alkyl; R² Selected from H, C_1- C₃ Alkyl and C substituted with 1 to 3 -OH groups_1- C₃ Alkyl; or R¹ and R² Together with the carbon to which it is attached, it can form a 3-6 membered cycloalkyl ring; t is 0, 1 or 2; Each R³ When present, a substituent on the ring to which -L-W is directly attached, wherein each R³ Independently selected from halogen, CN, C_1- C₃ Alkoxy, C_1- C₃ Alkyl, C(=O)OR¹⁰ and C(=O)NR¹³ R¹⁴ ； R⁴ For H, C_1- C₃ Alkyl, C_3- C₆ Cycloalkyl, -(CH₂ )₂ O(CH₂ )₂ Br or 1 to 2 independently selected from -OH, -C(=O)R¹⁵ and R¹⁰ C substituted with a group_1- C₃ Alkyl; Each R⁵ Independently selected from halogen, -CN, hydroxyl, -NR¹³ R¹⁴ 、C_3- C₆ Cycloalkyl, C_1- C₃ Alkoxy, C_1- C₃ Haloalkyl and optionally 1 to 3 R⁶ Group substituted C_1- C₃ Alkyl, where R^B Through two R⁵ Replace and each R⁵ 1 to 3 Rs depending on the situation⁶ Group substituted C_1- C₃ When the alkyl group is directly attached to the same carbon atom, it can form, together with the two directly attached carbon atoms, 1 to 3 R⁶ 3-5 membered cycloalkyl ring substituted with a radical; Each R⁶ Each occurrence is independently selected from halogen, hydroxyl, CN, C_1- C₃ Alkoxy, C_1- C₃ Alkyl and C_3- C₅ Cycloalkyl, or two R⁶ The group together with the two carbon atoms to which it is directly attached may form a 3-5 membered cycloalkyl ring or contain O, N or S as ring members and optionally 1 to 2 independently selected pendoxy groups and C_1- C₃ 4-6 membered heterocyclic ring substituted with an alkyl group; L is C₁ -C₄ A straight or branched chain alkyl linkage, or when W is a substituted ring, L may be C₁ -C₄ Straight chain or branched chain alkyl bond or single bond; W is H, -OH, -OR¹⁰ 、-C(=O)NR¹³ R¹⁴ 、-C(=O)O R¹³ 、-NR¹³ R¹⁴ 、-NR¹³ C(=O)OR¹⁰ 、-NR¹³ C(=O)R¹⁰ 、-SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹⁰ 、-P(=O)(OR¹³ )₂ 、-S(=O)R¹⁰ 、-S(=O)(=NR¹³ )R¹⁰ 、-CR¹¹ R¹² C(=O)NR¹³ R¹⁴ 、-CR¹¹ R¹² C(=O)OR¹³ 、-CR¹¹ R¹² NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹³ C(=O)OR¹⁰ 、-CR¹¹ R¹² NR¹³ C(=O)R¹⁰ 、-CR¹¹ R¹² SO₂ R¹⁰ 、-CR¹¹ R¹² SO₂ NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹³ SO₂ R¹⁰ 、-CR¹¹ R¹² P(=O)(OR¹³ )₂ 、-CR¹¹ R¹² S(=O)R¹⁰ 、-CR¹¹ R¹² S(=O)(=NR¹³ )R¹⁰ 、3-6 membered cycloalkyl、phenyl、containing one or two independently selected from N、NH、NR¹⁷ , O or S ring member 5-6 membered heterocycloalkyl, containing one or two independently selected from N, NH, NR¹⁷ , O or S as ring members or 5-membered heteroaryl groups fused to phenyl groups, which have 1 to 4 heteroatoms selected from N, O and S as ring members, wherein the 3-6-membered cycloalkyl, phenyl, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkyl and 5-membered heteroaryl groups of W are each substituted with 1 to 3 groups independently selected from the following groups: C_1- C₃ Alkyl, pendoxy, halogen, C_1- C₃ Halogen, -OH, -OR¹⁰ 、-OC(=O)NR¹³ R¹⁴ 、-SO₂ R¹⁰ 、-SO₂ NR¹⁴ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-SO₂ N=CR¹³ NR¹³ R¹⁴ 、-SO₂ NR¹³ C(=O)R¹⁰ 、-C(=O)NR¹³ SO₂ R¹⁰ 、-S(=O)R¹⁰ 、-S(=O)(=NR¹³ )R¹⁰ 、-NR¹³ SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹⁰ 、-NR¹³ R¹⁴ 、-NR¹³ C(=O)R¹³ 、-NR¹³ C(=O)OR¹⁰ 、-C(=O) NR¹³ R¹⁴ and -C(=O)OR¹³ ； R¹⁰ Selected from C_1- C₅ Alkyl, C_1- C₃ Haloalkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, containing one or two heteroatoms independently selected from N, NH, NR¹⁷ , O or S as ring members, and containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring members of 4-6 membered heterocyclic ring, wherein each R¹⁰ Substituted with 1 to 5 groups independently selected from the following groups: C_1- C₄ Alkyl, deuterium, C_1- C₄ Halogen alkoxy, -OH, -CN, -OC(=O)R¹⁴ 、-L³ OR¹³ 、C_1- C₂ Halogenyl, pendoxyl, -halogen, -C_1- C₃ Alkoxy, -OC(=O)NR¹³ R¹⁴ 、-SO₂ R¹³ 、-SO₂ NR¹³ R¹⁴ 、-SO₂ NR¹³ C(=O)R¹³ 、-C(=O)NR¹³ SO₂ R¹³ 、-S(=O)R¹³ 、-S(=O)(=NR¹⁴ )R¹³ 、-NR¹³ SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹³ 、-NR¹³ R¹⁴ 、-NR¹⁴ C(=O)R¹³ 、-NR¹⁴ C(=O)OR¹³ 、-C(=O)NR¹³ R¹⁴ 、-C(=O)OR¹³ , -(containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S as a ring member of a 4-7 membered heterocycloalkyl group), -(containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 member heterocyclic group), -C_3- C₅ Cycloalkyl and -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms including 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein the C_1- C₄ Alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclo, C_3- C₅ The cycloalkyl and 5-6 membered heteroaryl rings are each further substituted with 1 to 3 groups independently selected from the following groups: halogen, C_1- C₃ Alkyl, C_1- C₃ Halogen alkyl, -OR¹³ 、-CN and -NR¹³ R¹⁴ ； R¹¹ and R¹² Each independently selected from H and C_1- C₄ Alkyl; Each R¹³ Independently selected from H, C_1- C₄ Alkyl, containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 membered heterocycloalkyl, containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 member heterocyclic group and C_3- C₆ Cycloalkyl, wherein the C_1- C₄ Alkyl, heterocyclic and C_3- C₆ Cycloalkyl is optionally substituted with 1 to 3 groups independently selected from the following groups: C_1- C₄ Alkyl, halogen, -OH, -NR¹⁵ R¹⁶ 、-C(=O)OR¹⁵ 、C_1- C₂ Alkoxy and C substituted with 1 to 2 hydroxyl groups_1- C₄ Alkyl; R¹⁴ Selected from H, C_1- C₄ Alkyl and C_3- C₆ Cycloalkyl, wherein the C_1- C₄ Alkyl and C_3- C₆ Cycloalkyl is optionally substituted with 1 to 3 groups independently selected from the following groups: C_1- C₄ Alkyl, halogen, -OH, -NR¹⁵ R¹⁶ 、C_1- C₂ Alkoxy and C substituted with 1 to 2 hydroxyl groups_1- C₄ Alkyl; or R¹³ and R¹⁴ Together with the two directly attached nitrogen atoms, a ring may be formed which optionally contains additional N, O or S as a ring member and optionally is substituted by one to three selected from C_1- C₂ Alkyl, C_1- C₂ 4-6 membered ring substituted with alkoxy, pendoxy and hydroxyl groups; R¹⁵ and R¹⁶ Each independently selected from H and C_1- C₄ Alkyl; L³ For a key or direct link or branch link C_1- C₃ Alkylene; and 『' indicates a single key or double keys.Embodiment twenty three. A compound of formula (II) according to any one of Examples 1 to 22, or a pharmaceutically acceptable salt thereof, wherein: R^B is phenyl, pyridyl, thienyl or 5-8 membered cycloalkyl, where R^B 1 to 3 Rs depending on the situation⁵ Group substitution; R¹ Selected from H, C_1- C₃ Alkyl and C substituted with 1 to 3 -OH groups_1- C₃ Alkyl; R² is H; t is 0, 1 or 2; Each R³ When present, a substituent on the ring to which -L-W is directly attached, wherein each R³ Independently selected from C_1- C₃ Alkyl; R⁴ For H, C_1- C₃ Alkyl, C_3- C₆ Cycloalkyl, -(CH₂ )₂ O(CH₂ )₂ Br or 1 to 2 independently selected from -OH, -C(=O)R¹⁵ and R¹⁰ C substituted with a group_1- C₃ Alkyl; Each R⁵ Independently selected from halogen, -CN, C_1- C₃ Alkoxy and C_1- C₃ Alkyl; L is C₁ -C₄ A straight or branched chain alkyl linkage, or when W is a substituted ring, L may be C₁ -C₄ A straight chain or branched chain alkyl linkage or a single bond; W is a 3-6 membered cycloalkyl group, wherein the 3-6 membered cycloalkyl group is substituted by 1 to 3 groups independently selected from the following: -SO₂ R¹⁰ 、-SO₂ NR¹⁴ R¹⁰ 、-SO₂ NR¹³ R¹⁴ and-SO₂ N=CR¹³ NR¹³ R¹⁴ ; R¹⁰ Selected from C_1- C₅ Alkyl, C_1- C₃ Haloalkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, containing one or two heteroatoms independently selected from N, NH, NR¹⁷ , O or S as ring members, and containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring members of 4-6 membered heterocyclic ring, wherein each R¹⁰ Substituted with 1 to 5 groups independently selected from the following groups: C_1- C₄ Alkyl, deuterium, C_1- C₄ Halogen alkoxy, -OH, -CN, -OC(=O)R¹⁴ 、-L³ OR¹³ 、-NR¹³ R¹⁴ 、-NR¹⁴ C(=O)R¹³ 、-NR¹⁴ C(=O)OR¹³ 、-C(=O)NR¹³ R¹⁴ 、-C(=O) OR¹³ 、(containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S as ring members, 4-7 membered heterocycloalkyl, (containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S as a ring member of a 4-7 member heterocyclic group) and -C_3- C₅ Cycloalkyl, wherein the C_1- C₄ Alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclo and C_3- C₅ Cycloalkyl groups may be further substituted with 1 to 3 groups independently selected from the following groups: halogen, -OR¹³ and-NR¹³ R¹⁴ ； R¹¹ and R¹² Each independently selected from H and C_1- C₄ Alkyl; Each R¹³ Independently selected from H, C_1- C₄ Alkyl, containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 membered heterocycloalkyl, containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 member heterocyclic group and C_3- C₆ Cycloalkyl, wherein the C_1- C₄ Alkyl, heterocyclic and C_3- C₆ Cycloalkyl is optionally substituted with 1 to 3 groups independently selected from the following groups: C_1- C₄ Alkyl, halogen, -OH, -NR¹⁵ R¹⁶ 、-C(=O)OR¹⁵ and C substituted with 1 to 2 hydroxyl groups_1- C₄ Alkyl; R¹⁴ Selected from H and C_1- C₄ Alkyl; R¹⁵ and R¹⁶ Each independently selected from H and C_1- C₄ Alkyl; L³ For a key or direct link or branch link C_1- C₃ Alkylene; and 『' indicates a single key or double keys.Embodiment twenty four. A compound of formula (I) or formula (II) having a structure of formula (IIIa), formula (IIIb) or formula (IIIc), or a pharmaceutically acceptable salt thereof: , W, L, t, R¹ 、R³ and R⁵ As defined for formula (I); or W, L, t, R¹ 、R³ and R⁵ As defined in Example 22, or W, L, t, R¹ 、R³ and R⁵ As defined in Example 23.Embodiment 25. A compound of formula (I) or formula (II) having a structure of formula (IIIa), or a pharmaceutically acceptable salt thereof: W, L, t, R¹ 、R³ and R⁵ As defined for formula (I); or W, L, t, R¹ 、R³ and R⁵ As defined in Example 22, or W, L, t, R¹ 、R³ and R⁵ As defined in Example 23.Embodiment 26. A compound of any one of Examples 1 to 25, or a pharmaceutically acceptable salt thereof, wherein: R¹ Selected from H, C_1- C₃ Alkyl and C substituted with a -OH group_1- C₃ Alkyl; t is 0, 1 or 2; Each R³ When present, a substituent on the ring to which -L-W is directly attached, wherein each R³ Independently selected from halogen, CN, C_1- C₃ Alkoxy, C_1- C₃ Alkyl, C(=O)OR¹⁰ and C(=O)NR¹³ R¹⁴ ; Each R⁵ Independently selected from halogen, CN, C_1- C₃ Alkyl and C_1- C₃ Alkoxy; L is C₁ -C₄ Straight chain or branched chain alkyl linkage group; W is -SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-NR¹⁴ SO₂ R¹⁰ 、-CR¹¹ R¹² SO₂ R¹⁰ 、-CR¹¹ R¹² SO₂ NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹⁴ SO₂ R¹⁰ or an optionally substituted 3-6 membered cycloalkyl group; wherein the optionally substituted cycloalkyl group has 1 to 3 substituents independently selected from the following groups: C_1- C₃ Alkyl, pendoxy, halogen, -OH, -SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-SO₂ NR¹⁴ R¹⁰ 、-NR¹³ SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹⁰ 、-NR¹³ R¹⁴ 、-OR¹⁰ 、-NR¹³ C(=O)OR¹⁰ 、-C(=O)NR¹³ R¹⁴ and C(=O)OR¹³ , R¹⁰ Selected from C_1- C₅ Alkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, containing one or two heteroatoms independently selected from N, NH, NR¹⁷ , O or S as ring members, and containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring members of 4-6 membered heterocyclic ring, wherein each R¹⁰ Substituted with 1 to 4 groups selected from the following groups as appropriate: C_1- C₃ Alkyl, pendoxy, CN, halogen, C_1- C₃ Alkoxy, OH and C_3- C₅ Cycloalkyl; R¹¹ and R¹² Each independently selected from H and C_1- C₄ Alkyl; Each R¹³ Independently selected from H and optionally halogen, -OH or C_1- C₂ Alkoxy substituted C_1- C₄ Alkyl; R¹⁴ Selected from H and C_1- C₄ Alkyl; or R¹³ and R¹⁴ Together with the two directly attached nitrogen atoms, a ring may be formed which optionally contains additional N, O or S as a ring member and optionally is substituted by one or two selected from C_1- C₂ Alkyl, C_1- C₂ 4-6 membered ring substituted with alkoxy, pendoxy and hydroxyl groups.Embodiment 27. A compound of any one of Examples 1 to 25, or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, methyl or methyl substituted by a -OH group; t is 0, 1 or 2; each R³ When present, a substituent on the ring to which -L-W is directly attached, wherein each R³ Independently selected from methyl groups; Each R⁵ Independently selected from Cl, F, -CN, methyl and -OCH₃ ; L is -CH₂ -or-CH₂ CH₂ -; W is cyclopropyl substituted -SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ or -SO₂ NR¹⁴ R¹⁰ ; R¹⁰ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isoxazolyl, oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, oxolinyl, piperidinyl, piperonyl, pyrrolidinyl and azocyclobutane, wherein each R¹⁰ Substituted with 1 to 4 groups independently selected from the following groups: methyl, ethyl, deuterium, -OCH₃ 、-OH、-OCHF₂ 、-CN、-NH₂ 、-NHCH₃ 、-N(CH₃ )₂ 、-NHR¹³ 、-NHCH(=O), -NHC(=O)CH₃ 、-NHC(=O)OCH₃ 、-NHC(=O)CH₂ NH₂ 、-NHC(=O)CH₂ N(CH₃ )₂ 、-NHC(=O)CH(CH₃ )NH₂ 、-NHC(=O)C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ OH, -OCH₂ CH(CH₃ )OH, -OCH₂ CH(CH₃ )₂ OH, -OCH(F)CH₂ OH, -OCF₂ CH₂ OH, -OCH₂ CH₂ NH₂ 、-OCH₂ CH(CH₃ )NH₂ 、-OCH₂ C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ NHCH₃ 、-OCH₂ CH₂ N(CH₃ )₂ 、-OCH(F)CH₂ NH₂ 、-OCF₂ CH₂ NH₂ 、-CH₂ OCH₂ CH₂ NH₂ 、-CH₂ CH₂ OH, -CH₂ OH, -CH₂ NH₂ 、-O-nitrocyclobutane、-C(=O)NH₂ 、-C(=O)NHCH₃ 、-OC(=O)CH₃ , cyclopropyl, azacyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl, wherein the methyl, ethyl, cyclopropyl, azacyclobutanyl, Pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl are each optionally further substituted with 1 to 3 groups independently selected from the following: F, -OH, -OCH₃ 、-NH₂ and methyl; R¹³ Selected from H, methyl, ethyl, isopropyl, propyl, butyl, isobutyl, pentyl, a 7-membered heterocyclic ring containing 1 to 2 heteroatoms independently selected from N, O or S as ring members, and C_3- C₆ Cycloalkyl, wherein the methyl, ethyl, isopropyl, propyl, butyl, isobutyl, pentyl, heterocyclic and C_3- C₆ Cycloalkyl is optionally substituted by 1 to 3 groups independently selected from the following groups: methyl, ethyl, propyl, isopropyl, F, -OH, -NH₂ 、-N(CH₃ )₂ 、-C(=O)OH、C_1- C₂ Alkoxy and C substituted with 1 to 2 hydroxyl groups_1- C₄ Alkyl, and R¹⁴ is selected from H and methyl.Embodiment 28. A compound of formula (I) or formula (II) having a structure of formula (IVa), formula (IVb) or formula (IVc), or a pharmaceutically acceptable salt thereof: Among them: L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined for formula (I); or L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 22; or L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 23; or L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 26, or L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 27.Embodiment 29. A compound of formula (I) or formula (II) having a structure of formula (IVa), or a pharmaceutically acceptable salt thereof: Among them: L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined for formula (I); or L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 22; or L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 23; or L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 26, or L, R¹ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 27.Embodiment 30. A compound of formula (I) or formula (II) having a structure of formula (Va), formula (Vb) or formula (Vc), or a pharmaceutically acceptable salt thereof: Among them: L, R¹ 、R⁵ and R¹⁰ As defined for formula (I); or L, R¹ 、R⁵ and R¹⁰ As defined in Example 22; or L, R¹ 、R⁵ and R¹⁰ As defined in Example 23; or L, R¹ 、R⁵ and R¹⁰ As defined in Example 26, or L, R¹ 、R⁵ and R¹⁰ As defined in Example 27.Embodiment 31. A compound of formula (I) or formula (II) having a structure of formula (Va), or a pharmaceutically acceptable salt thereof: Among them: L, R¹ 、R⁵ and R¹⁰ As defined for formula (I); or L, R¹ 、R⁵ and R¹⁰ As defined in Example 22; or L, R¹ 、R⁵ and R¹⁰ As defined in Example 23; or L, R¹ 、R⁵ and R¹⁰ As defined in Example 26, or L, R¹ 、R⁵ and R¹⁰ As defined in Example 27.Embodiment 32. A compound of any one of Examples 1 to 31, or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, methyl or methyl substituted by a -OH group; each R⁵ Independently selected from Cl, F and -CN; L is a bond or CH₂ or CH₂ CH₂ ; R¹⁰ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isoxazolyl, oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, oxolinyl, piperidinyl, piperonyl, pyrrolidinyl and azocyclobutane, wherein each R¹⁰ Substituted with 1 to 4 groups independently selected from the following groups: methyl, ethyl, deuterium, -OCH₃ 、-OH、-OCHF₂ 、-CN、-NH₂ 、-NHCH₃ 、-N(CH₃ )₂ 、-NHR¹³ 、-NHCH(=O), -NHC(=O)CH₃ 、-NHC(=O)OCH₃ 、-NHC(=O)CH₂ NH₂ 、-NHC(=O)CH₂ N(CH₃ )₂ 、-NHC(=O)CH(CH₃ )NH₂ 、-NHC(=O)C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ OH, -OCH₂ CH(CH₃ )OH, -OCH₂ CH(CH₃ )₂ OH, -OCH(F)CH₂ OH, -OCF₂ CH₂ OH, -OCH₂ CH₂ NH₂ 、-OCH₂ CH(CH₃ )NH₂ 、-OCH₂ C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ NHCH₃ 、-OCH₂ CH₂ N(CH₃ )₂ 、-OCH(F)CH₂ NH₂ 、-OCF₂ CH₂ NH₂ 、-CH₂ OCH₂ CH₂ NH₂ 、-CH₂ CH₂ OH, -CH₂ OH, -CH₂ NH₂ 、-O-nitrocyclobutane、-C(=O)NH₂ 、-C(=O)NHCH₃ 、-OC(=O)CH₃ , cyclopropyl, azacyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl, wherein the methyl, ethyl, cyclopropyl, azacyclobutanyl, Pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl are each optionally further substituted with 1 to 3 groups independently selected from the following: F, -OH, -OCH₃ 、-NH₂ and and R¹¹ and R¹² Each independently represents H or methyl.Embodiment 33. A compound of any one of Examples 1 to 32, or a pharmaceutically acceptable salt thereof, wherein: R¹ is H, methyl or methyl substituted by a -OH group; each R⁵ Independently selected from Cl, F and -CN; L is a bond or CH₂ or CH₂ CH₂ ; and R¹⁰ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isoxazolyl, oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, oxolinyl, piperidinyl, piperonyl, pyrrolidinyl and azocyclobutane, wherein each R¹⁰ Substituted with 1 to 4 groups independently selected from the following groups: methyl, ethyl, deuterium, -OCH₃ 、-OH、-OCHF₂ 、-CN、-NH₂ 、-NHCH₃ 、-N(CH₃ )₂ 、-NHR¹³ 、-NHCH(=O), -NHC(=O)CH₃ 、-NHC(=O)OCH₃ 、-NHC(=O)CH₂ NH₂ 、-NHC(=O)CH₂ N(CH₃ )₂ 、-NHC(=O)CH(CH₃ )NH₂ 、-NHC(=O)C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ OH, -OCH₂ CH(CH₃ )OH, -OCH₂ CH(CH₃ )₂ OH, -OCH(F)CH₂ OH, -OCF₂ CH₂ OH, -OCH₂ CH₂ NH₂ 、-OCH₂ CH(CH₃ )NH₂ 、-OCH₂ C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ NHCH₃ 、-OCH₂ CH₂ N(CH₃ )₂ 、-OCH(F)CH₂ NH₂ 、-OCF₂ CH₂ NH₂ 、-CH₂ OCH₂ CH₂ NH₂ 、-CH₂ CH₂ OH, -CH₂ OH, -CH₂ NH₂ 、-O-nitrocyclobutane、-C(=O)NH₂ 、-C(=O)NHCH₃ 、-OC(=O)CH₃ , cyclopropyl, azacyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl, wherein the methyl, ethyl, cyclopropyl, azacyclobutanyl, Pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl are each optionally further substituted with 1 to 3 groups independently selected from the following: F, -OH, -OCH₃ 、-NH₂ .Embodiment 34. A compound of formula (I) having a structure of formula (VI), or a pharmaceutically acceptable salt thereof, W, L, t, R³ 、R⁴ and R^B As defined for formula (I).Embodiment 35. A compound of formula (VII), or a pharmaceutically acceptable salt thereof, Where: R^C H or 1 to 3 Rs depending on the situation⁶ Group substituted C₁ -C₆ Alkyl; t is 0, 1 or 2; Each R³ When present, a substituent on the ring to which -L-W is directly attached, wherein each R³ Independently selected from halogen, CN, C_1- C₃ Alkoxy, C_1- C₃ Alkyl, C(=O)OR¹⁰ and C(=O)NR¹³ R¹⁴ ； R⁴ H, halogen or C_1-3 Alkyl; L is C₁ -C₄ Straight chain or branched chain alkyl bond or single bond; W is H, -OH, -OR¹⁰ 、-C(=O)NR¹³ R¹⁴ 、-C(=O)O R¹³ 、-NR¹³ R¹⁴ 、-NR¹³ C(=O)OR¹⁰ 、-NR¹³ C(=O)R¹⁰ 、-SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹⁰ 、-P(=O)(OR¹³ )₂ 、-S(=O)R¹⁰ 、-S(=O)(=NR¹³ )R¹⁰ 、-CR¹¹ R¹² C(=O)NR¹³ R¹⁴ 、-CR¹¹ R¹² C(=O)OR¹³ 、-CR¹¹ R¹² NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹³ C(=O)OR¹⁰ 、-CR¹¹ R¹² NR¹³ C(=O)R¹⁰ 、-CR¹¹ R¹² SO₂ R¹⁰ 、-CR¹¹ R¹² SO₂ NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹³ SO₂ R¹⁰ 、-CR¹¹ R¹² P(=O)(OR¹³ )₂ 、-CR¹¹ R¹² S(=O)R¹⁰ 、-CR¹¹ R¹² S(=O)(=NR¹³ )R¹⁰ 、3-6 membered cycloalkyl、phenyl、containing one or two independently selected from N、NH、NR¹⁷ , O or S ring member 5-6 membered heterocycloalkyl, containing one or two independently selected from N, NH, NR¹⁷ , O or S as ring members or 5-membered heteroaryl groups fused to phenyl groups, which have 1 to 4 heteroatoms selected from N, O and S as ring members, wherein the 3-6-membered cycloalkyl, phenyl, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkyl and 5-membered heteroaryl groups of W are each substituted with 1 to 3 groups independently selected from the following groups: C_1- C₃ Alkyl, pendoxy, halogen, C_1- C₃ Halogen, -OH, -OR¹⁰ 、-OC(=O)NR¹³ R¹⁴ 、-SO₂ R¹⁰ 、-SO₂ NR¹⁴ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-SO₂ N=CR¹³ NR¹³ R¹⁴ 、-SO₂ NR¹³ C(=O)R¹⁰ 、-C(=O)NR¹³ SO₂ R¹⁰ 、-S(=O)R¹⁰ 、-S(=O)(=NR¹³ )R¹⁰ 、-NR¹³ SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹⁰ 、-NR¹³ R¹⁴ 、-NR¹³ C(=O)R¹³ 、-NR¹³ C(=O)OR¹⁰ 、-C(=O)NR¹³ R¹⁴ and -C(=O)OR¹³ ； R¹⁰ Selected from C_1- C₅ Alkyl, C_1- C₃ Haloalkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, containing one or two heteroatoms independently selected from N, NH, NR¹⁷ , O or S as ring members, and containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring members of 4-6 membered heterocyclic ring, wherein each R¹⁰ Substituted with 1 to 5 groups independently selected from the following groups: C_1- C₄ Alkyl, deuterium, C_1- C₄ Halogen alkoxy, -OH, -CN, -OC(=O)R¹⁴ 、-L³ OR¹³ 、C_1- C₂ Halogenyl, pendoxyl, -halogen, -C_1- C₃ Alkoxy, -OC(=O)NR¹³ R¹⁴ 、-SO₂ R¹³ 、-SO₂ NR¹³ R¹⁴ 、-SO₂ NR¹³ C(=O)R¹³ 、-C(=O)NR¹³ SO₂ R¹³ 、-S(=O)R¹³ 、-S(=O)(=NR¹⁴ )R¹³ 、-NR¹³ SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹³ 、-NR¹³ R¹⁴ 、-NR¹⁴ C(=O)R¹³ 、-NR¹⁴ C(=O)OR¹³ 、-C(=O)NR¹³ R¹⁴ 、-C(=O)OR¹³ 、(containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S as ring members, 4-7 membered heterocycloalkyl, (containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 member heterocyclic group), -C_3- C₅ Cycloalkyl and -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms including 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein the C_1- C₄ Alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclo, C_3- C₅ The cycloalkyl and 5-6 membered heteroaryl rings are each further substituted with 1 to 3 groups independently selected from the following groups: halogen, C_1- C₃ Alkyl, C_1- C₃ Halogen alkyl, -OR¹³ 、-CN and -NR¹³ R¹⁴ ； R¹¹ and R¹² Each independently selected from H and C_1- C₄ Alkyl; Each R¹³ Independently selected from H, optionally halogen, -OH, amine or C_1-2 Alkoxy substituted C_1-4 Alkyl and optionally halogen, -OH, amino or C_1-2 Alkoxy substituted_3-6 Alkyl; R¹⁴ Independently selected from H, optionally halogen, -OH, amine or C_1-2 Alkoxy substituted C_1-4 Alkyl and optionally halogen, -OH, amino or C_1-2 Alkoxy substituted_3-6 Alkyl; or R¹³ and R¹⁴ Together with the two directly attached nitrogen atoms, a ring may be formed which optionally contains additional N, O or S as a ring member and optionally is substituted by one to three selected from C_1-2 Alkyl, C_1-2 4-6 membered ring substituted with alkoxy, pendoxy and hydroxyl groups; L³ For a key or direct link or branch link C_1-3 Alkylene; Each R⁶ Each occurrence is independently selected from halogen, hydroxyl, CN, C_1- C₃ Alkoxy, C_1- C₃ Alkyl and C_3- C₅ Cycloalkyl, or two R⁶ The group together with the two carbon atoms to which it is directly attached may form a 3-5 membered cycloalkyl ring or contain O, N or S as ring members and optionally 1 to 2 independently selected pendoxy groups and C_1- C₃ A 4-6 membered heterocyclic ring substituted with an alkyl group.Embodiment 36. The compound of formula (VII) of Example 35, or a pharmaceutically acceptable salt thereof, wherein R^C is H, methyl, ethyl, propyl, isopropyl, t-butyl or n-butyl.Embodiment 37. A compound of any one of Examples 34 to 36, or a pharmaceutically acceptable salt thereof, wherein: L is C₁ -C₄ Straight chain or branched chain alkyl linkage group; W is -SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-NR¹⁴ SO₂ R¹⁰ 、-CR¹¹ R¹² SO₂ R¹⁰ 、-CR¹¹ R¹² SO₂ NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹⁴ SO₂ R¹⁰ Or replaced by C as appropriate₁ -C₃ Alkyl or optionally substituted 3-6 membered cycloalkyl; Wherein the optionally substituted C₁ -C₃ The substituents of the alkyl group and the cycloalkyl group which are optionally substituted are 1 to 3 groups independently selected from the following groups: C_1- C₃ Alkyl, pendoxy, halogen, -OH, -SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-SO₂ NR¹⁴ R¹⁰ 、-NR¹³ SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹⁰ 、-NR¹³ R¹⁴ 、-OR¹⁰ 、-NR¹³ C(=O)OR¹⁰ 、-C(=O)NR¹³ R¹⁴ and C(=O)OR¹³ ; R¹⁰ Selected from C_1- C₅ Alkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, containing one or two heteroatoms independently selected from N, NH, NR¹⁷ , O or S as ring members, and containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring members of 4-6 membered heterocyclic ring, wherein each R¹⁰ C is substituted with 1 to 4 groups selected from the following groups as appropriate_1- C₃ Alkyl, pendoxy, CN, halogen, C_1- C₃ Alkoxy, OH and C_3- C₅ Cycloalkyl; R¹¹ and R¹² Each independently selected from H and C_1- C₄ Alkyl; Each R¹³ Independently selected from H and optionally halogen, -OH or C_1- C₂ Alkoxy substituted C_1- C₄ Alkyl; R¹⁴ Selected from H and C_1- C₄ Alkyl; or R¹³ and R¹⁴ Together with the two directly attached nitrogen atoms, a ring may be formed which optionally contains additional N, O or S as a ring member and optionally is substituted by one or two selected from C_1- C₂ Alkyl, C_1- C₂ 4-6 membered ring substituted with alkoxy, pendoxy and hydroxyl groups.Embodiment 38. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B Selected from phenyl, pyridyl, thienyl and cyclohexyl, each of which may have 1 to 3 R⁵ Group substitution.Embodiment 39. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Group-substituted pyridinyl.Embodiment 40. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Group-substituted pyridin-3-yl.Embodiment 41. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Group-substituted pyridin-2-yl.Embodiment 42. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Group-substituted thienyl.Embodiment 43. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Group-substituted thiophene-2-yl.Embodiment 44. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Cyclohexyl substituted with radicals.Embodiment 45. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Group-substituted phenyl.Embodiment 46. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B Selected from phenyl, pyridyl, thienyl and cyclohexyl, each of which may have 1 to 3 R⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Alkyl and -CN group substitution.Embodiment 47. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Group-substituted pyridin-3-yl.Embodiment 48. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Pyridin-2-yl substituted with alkyl and -CN groups.Embodiment 49. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Thienyl substituted with alkyl and -CN groups.Embodiment 50. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Thiophene-2-yl substituted with alkyl and -CN groups.Embodiment 51. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Cyclohexyl substituted with alkyl and -CN groups.Embodiment 52. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Phenyl substituted with alkyl and -CN groups.Embodiment 53. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B Selected from phenyl, pyridyl, thienyl and cyclohexyl, each of which may have 1 to 3 R⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN group substitution.Embodiment 54. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted pyridin-2-yl.Embodiment 55. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted thienyl groups.Embodiment 56. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted thiophene-2-yl.Embodiment 57. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted cyclohexyl.Embodiment 58. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 3 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted phenyl.Embodiment 59. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B Selected from phenyl, pyridyl, thienyl and cyclohexyl, each of which may be optionally substituted with 1 to 2 R⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Alkyl and -CN group substitution.Embodiment 60. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Group-substituted pyridin-3-yl.Embodiment 61. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Pyridin-2-yl substituted with alkyl and -CN groups.Embodiment 62. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Thienyl substituted with alkyl and -CN groups.Embodiment 63. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Thiophene-2-yl substituted with alkyl and -CN groups.Embodiment 64. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Cyclohexyl substituted with alkyl and -CN groups.Embodiment 65. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from halogen, C_1- C₃ Alkoxy, C_1- C₃ Phenyl substituted with alkyl and -CN groups.Embodiment 66. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted pyridin-2-yl.Embodiment 67. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted thienyl groups.Embodiment 68. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted thiophene-2-yl.Embodiment 69. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted cyclohexyl.Embodiment 70. A compound of formula (I), or a compound according to any one of Examples 1 to 34, or a pharmaceutically acceptable salt thereof, wherein R^B 1 to 2 Rs depending on the situation⁵ Independently selected from Cl, F, -OCH₃ , methyl and -CN substituted phenyl.Embodiment 71. A compound of any one of Examples 38, 45, 46, 52, 53, 58, 59, 65 or 70, or a pharmaceutically acceptable salt thereof, wherein the phenyl ring R^B The above substituents are at the meta position and/or para position of the phenyl ring.Embodiment 72. A compound of any one of Examples 1-34, 38, 45, 46, 52, 53, 58, 59, 65 or 70, or a pharmaceutically acceptable salt thereof, wherein R^B Selected from:.Embodiment 73. A compound of any one of Examples 1-34, 38, 45, 46, 52, 53, 58, 59, 65 or 70, or a pharmaceutically acceptable salt thereof, wherein R^B Selected from:.Embodiment 74. A compound of formula (I), or a compound according to any one of Examples 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R¹ is H.Embodiment 75. A compound of formula (I), or a compound according to any one of Examples 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R¹ For C_1- C₃ Alkyl.Embodiment 76. A compound of formula (I), or a compound according to any one of Examples 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R¹ It is a methyl group.Embodiment 77. A compound of formula (I), or a compound according to any one of Examples 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R¹ C substituted with 1 to 3 -OH groups_1- C₃ Alkyl.Embodiment 78. A compound of formula (I), or a compound according to any one of Examples 1 to 73, or a pharmaceutically acceptable salt thereof, wherein R¹ For -CH₂ OH.Embodiment 79. A compound of formula (I) or a compound according to any one of Examples 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R² is H.Embodiment 80. A compound of formula (I), or a compound according to any one of Examples 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R² For C_1- C₃ Alkyl.Embodiment 81. A compound of formula (I), or a compound according to any one of Examples 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R² It is a methyl group.Embodiment 82. A compound of formula (I), or a compound according to any one of Examples 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R² C substituted with 1 to 3 -OH groups_1- C₃ Alkyl.Embodiment 83. A compound of formula (I), or a compound according to any one of Examples 1 to 78, or a pharmaceutically acceptable salt thereof, wherein R² For -CH₂ OH.Embodiment 84. A compound of formula (I), or a compound according to any one of Examples 1 to 83, or a pharmaceutically acceptable salt thereof, wherein each R³ Independently selected from halogen, CN, C_1- C₃ Alkoxy, C_1- C₃ Alkyl, C(=O)OR¹⁰ and C(=O)NR¹³ R¹⁴ .Embodiment 85. A compound of formula (I), or a compound according to any one of Examples 1 to 83, or a pharmaceutically acceptable salt thereof, wherein each R³ Independently selected from halogen, CN, C_1- C₃ Alkoxy and C_1- C₃ Alkyl.Embodiment 86. A compound of formula (I), or a compound according to any one of Examples 1 to 83, or a pharmaceutically acceptable salt thereof, wherein each R³ Independently selected from Cl, F, CN, -OCH₃ And methyl.Embodiment 87. A compound of formula (I), or a compound according to any one of Examples 1 to 83, or a pharmaceutically acceptable salt thereof, wherein R³ It is a methyl group.Embodiment 88. A compound of formula (I), or a compound according to any one of Examples 1 to 83, or a pharmaceutically acceptable salt thereof, wherein R³ Does not exist.Embodiment 89. A compound of formula (I), or a compound according to any one of Examples 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R⁴ For H, C_1- C₃ Alkyl, C_3- C₆ Cycloalkyl or 1 to 2 independently selected from -OH, -C(=O)R¹⁵ and R¹⁰ C substituted with a group_1- C₃ Alkyl.Embodiment 90. A compound of formula (I), or a compound according to any one of Examples 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R⁴ H, methyl, cyclopropyl, .Embodiment 91. A compound of formula (I), or a compound according to any one of Examples 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R⁴ H or C_1- C₃ Alkyl.Embodiment 92. A compound of formula (I), or a compound according to any one of Examples 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R⁴ H or methylEmbodiment 93. A compound of formula (I) or a compound according to any one of Examples 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R⁴ is H.Embodiment 94. A compound of formula (I) or a compound according to any one of Examples 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R⁴ It is a methyl group.Embodiment 95. A compound of formula (I), or a compound according to any one of Examples 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R⁴ 1 to 2 independently selected from -OH, -C(=O)R¹⁵ and R¹⁰ C substituted with a group_1- C₃ Alkyl.Embodiment 96. A compound of formula (I), or a compound according to any one of Examples 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R⁴ for .Embodiment 97. A compound of formula (I), or a compound according to any one of Examples 1 to 88, or a pharmaceutically acceptable salt thereof, wherein R⁴ For C_3- C₆ Cycloalkyl.Embodiment 98. A compound of formula (I), or a compound according to any one of Examples 1 to 87, or a pharmaceutically acceptable salt thereof, wherein R⁴ It is cyclopropyl.Embodiment 99. A compound of formula (I), or a compound according to any one of Examples 1 to 98, or a pharmaceutically acceptable salt thereof, wherein each R⁵ Independently selected from halogen, -CN, hydroxyl, -NR¹³ R¹⁴ 、C_3- C₆ Cycloalkyl, C_1- C₃ Alkoxy, C_1- C₃ Haloalkyl and optionally 1 to 3 R⁶ Group substituted C_1- C₃ Alkyl, wherein the group may be substituted with 1 to 3 R⁶ Group substituted C_1- C₃ When two alkyl groups are directly attached to the same carbon atom, they may form, together with the carbon atoms to which they are attached, 1 to 3 R⁶ 3-5 membered cycloalkyl ring substituted with radicals.Embodiment 100. A compound of formula (I), or a compound according to any one of Examples 1 to 98, or a pharmaceutically acceptable salt thereof, wherein each R⁵ Independently selected from halogen, -CN, C_1- C₃ Alkoxy and C_1- C₃ Alkyl.Embodiment 101. A compound of formula (I), or a compound according to any one of Examples 1 to 98, or a pharmaceutically acceptable salt thereof, wherein each R⁵ Independently selected from Cl, F, -CN, -OCH₃ And methyl.Embodiment 102. A compound of formula (I), or a compound according to any one of Examples 1 to 98, or a pharmaceutically acceptable salt thereof, wherein each R⁵ Independently selected from Cl and -CN.Embodiment 103. A compound of formula (I), or a compound according to any one of Examples 1 to 102, or a pharmaceutically acceptable salt thereof, wherein each R⁶ Each occurrence is independently selected from halogen, hydroxyl, CN, C_1- C₃ Alkoxy, C_1- C₃ Alkyl and C_3- C₅ Cycloalkyl.Embodiment 104. A compound of formula (I), or a compound according to any one of Examples 1 to 102, or a pharmaceutically acceptable salt thereof, wherein each R⁶ It is a hydroxyl group.Embodiment 105. A compound of formula (I) or a compound according to any one of Examples 1 to 104, or a pharmaceutically acceptable salt thereof, wherein W is H, -OH, -OR, -C(=O)NR¹³ R¹⁴ 、-C(=O)OR¹³ 、-NR¹³ R¹⁴ 、-NR¹³ C(=O)OR¹⁰ 、-NR¹³ C(=O)R¹⁰ 、-SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹⁰ 、-P(=O)(OR¹³ )₂ 、-S(=O)R¹⁰ 、-S(=O)(=NR¹³ )R¹⁰ 、-CR¹¹ R¹² C(=O)NR¹³ R¹⁴ 、-CR¹¹ R¹² C(=O)OR¹³ 、-CR¹¹ R¹² NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹³ C(=O)OR¹⁰ 、-CR¹¹ R¹² NR¹³ C(=O)R¹⁰ 、-CR¹¹ R¹² SO₂ R¹⁰ 、-CR¹¹ R¹² SO₂ NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹³ SO₂ R¹⁰ 、-CR¹¹ R¹² P(=O)(OR¹³ )₂ 、-CR¹¹ R¹² S(=O)R¹⁰ 、-CR¹¹ R¹² S(=O)(=NR¹³ )R¹⁰ 、3-6 membered cycloalkyl, phenyl, containing one or two independently selected from N, NH, NR¹⁷ , O or S ring member 5-6 membered heterocycloalkyl, containing one or two independently selected from N, NH, NR¹⁷ , O or S as ring members or 5-membered heteroaryl groups fused to phenyl groups, which have 1 to 4 heteroatoms selected from N, O and S as ring members, wherein the 3-6-membered cycloalkyl, phenyl, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkyl and 5-membered heteroaryl groups of W are each substituted with 1 to 3 groups independently selected from the following groups: C_1- C₃ Alkyl, pendoxy, halogen, C_1- C₃ Halogen alkyl, -L² OH, -L² OR¹⁰ 、-L² OC(=O)NR¹³ R¹⁴ 、-L² SO₂ R¹⁰ 、-L² SO₂ NR¹⁴ R¹⁰ 、-L² SO₂ NR¹³ R¹⁴ 、-L² SO₂ N=CR¹³ NR¹³ R¹⁴ 、-L² SO₂ NR¹³ C(=O)R¹⁰ 、-L² C(=O)NR¹³ SO₂ R¹⁰ 、-L² S(=O)R¹⁰ 、-L² S(=O)(=NR¹³ )R¹⁰ 、-L² NR¹³ SO₂ NR¹³ R¹⁴ 、-L² NR¹³ SO₂ R¹⁰ 、-L² NR¹³ R¹⁴ 、-L² NR¹³ C(=O)R¹³ 、-L² NR¹³ C(=O)OR¹⁰ 、-L² C(=O)NR¹³ R¹⁴ and -L² C(=O)OR¹³ .Embodiment 106. A compound of formula (I) or a compound according to any one of Examples 1 to 104, or a pharmaceutically acceptable salt thereof, wherein W is H, -OH, -OR, -C(=O)NR¹³ R¹⁴ 、-C(=O)OR¹³ 、-NR¹³ R¹⁴ 、-NR¹³ C(=O)OR¹⁰ 、-NR¹³ C(=O)R¹⁰ 、-SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹⁰ 、-P(=O)(OR¹³ )₂ 、-S(=O)R¹⁰ 、-S(=O)(=NR¹³ )R¹⁰ 、-CR¹¹ R¹² C(=O)NR¹³ R¹⁴ 、-CR¹¹ R¹² C(=O)OR¹³ 、-CR¹¹ R¹² NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹³ C(=O)OR¹⁰ 、-CR¹¹ R¹² NR¹³ C(=O)R¹⁰ 、-CR¹¹ R¹² SO₂ R¹⁰ 、-CR¹¹ R¹² SO₂ NR¹³ R¹⁴ 、-CR¹¹ R¹² NR¹³ SO₂ R¹⁰ 、-CR¹¹ R¹² P(=O)(OR¹³ )₂ 、-CR¹¹ R¹² S(=O)R¹⁰ or -CR¹¹ R¹² S(=O)(=NR¹³ )R¹⁰ .Embodiment 107. A compound of formula (I) or a compound according to any one of Examples 1 to 104, or a pharmaceutically acceptable salt thereof, wherein W is a 3-6 membered cycloalkyl, a phenyl, a cycloalkyl containing one or two independently selected from N, NH, NR¹⁷ , O or S ring member 5-6 membered heterocycloalkyl, containing one or two independently selected from N, NH, NR¹⁷ , O or S as ring members or 5-membered heteroaryl groups fused to phenyl groups, which have 1 to 4 heteroatoms selected from N, O and S as ring members, wherein the 3-6-membered cycloalkyl, phenyl, 5-6-membered heterocycloalkyl, 5-6-membered heterocycloalkyl and 5-membered heteroaryl groups of W are each substituted with 1 to 3 groups independently selected from the following groups: C_1- C₃ Alkyl, pendoxy, halogen, C_1- C₃ Halogen alkyl, -L² OH, -L² OR¹⁰ 、-L² OC(=O)NR¹³ R¹⁴ 、-L² SO₂ R¹⁰ 、-L² SO₂ NR¹⁴ R¹⁰ 、-L² SO₂ NR¹³ R¹⁴ 、-L² SO₂ N=CR¹³ NR¹³ R¹⁴ 、-L² SO₂ NR¹³ C(=O)R¹⁰ 、-L² C(=O)NR¹³ SO₂ R¹⁰ 、-L² S(=O)R¹⁰ 、-L² S(=O)(=NR¹³ )R¹⁰ 、-L² NR¹³ SO₂ NR¹³ R¹⁴ 、-L² NR¹³ SO₂ R¹⁰ 、-L² NR¹³ R¹⁴ 、-L² NR¹³ C(=O)R¹³ 、-L² NR¹³ C(=O)OR¹⁰ 、-L² C(=O)NR¹³ R¹⁴ and -L² C(=O)OR¹³ .Embodiment 108. A compound of formula (I) or a compound according to any one of Examples 1 to 104, or a pharmaceutically acceptable salt thereof, wherein W is a 3-6 membered cycloalkyl group substituted with 1 to 3 groups independently selected from the following groups: C_1- C₃ Alkyl, pendoxy, halogen, C_1- C₃ Halogen alkyl, -L² OH, -L² OR¹⁰ 、-L² OC(=O)NR¹³ R¹⁴ 、-L² SO₂ R¹⁰ 、-L² SO₂ NR¹⁴ R¹⁰ 、-L² SO₂ NR¹³ R¹⁴ 、-L² SO₂ N=CR¹³ NR¹³ R¹⁴ 、-L² SO₂ NR¹³ C(=O)R¹⁰ 、-L² C(=O)NR¹³ SO₂ R¹⁰ 、-L² S(=O)R¹⁰ 、-L² S(=O)(=NR¹³ )R¹⁰ 、-L² NR¹³ SO₂ NR¹³ R¹⁴ 、-L² NR¹³ SO₂ R¹⁰ 、-L² NR¹³ R¹⁴ 、-L² NR¹³ C(=O)R¹³ 、-L² NR¹³ C(=O)OR¹⁰ 、-L² C(=O)NR¹³ R¹⁴ and -L² C(=O)OR¹³ .Embodiment 109. A compound of formula (I) or a compound according to any one of Examples 1 to 104, or a pharmaceutically acceptable salt thereof, wherein W is alkyl-O₂ R¹⁰ 、-SO₂ NR¹⁴ R¹⁰ 、-SO₂ NR¹³ R¹⁴ or -SO₂ N=CR¹³ NR¹³ R¹⁴ Substituted cyclopropyl, -SO₂ NR¹³ C(=O)R¹⁰ 、-C(=O)NR¹³ SO₂ R¹⁰ 、-S(=O)R¹⁰ 、-S(=O)(=NR¹³ )R¹⁰ 、-NR¹³ SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹⁰ 、-NR¹³ R¹⁴ 、-NR¹³ C(=O)R¹³ 、-NR¹³ C(=O)OR¹⁰ 、-C(=O)NR¹³ R¹⁴ and -C(=O)OR¹³ .Embodiment 110. A compound of formula (I) or a compound according to any one of Examples 1 to 104, or a pharmaceutically acceptable salt thereof, wherein W is -SO₂ R¹⁰ 、-SO₂ NR¹⁴ R¹⁰ 、-SO₂ NR¹³ R¹⁴ or -SO₂ N=CR¹³ NR¹³ R¹⁴ Substituted cyclopropyl.Embodiment 111. A compound of formula (I) or a compound according to any one of Examples 1 to 104, or a pharmaceutically acceptable salt thereof, wherein the part W—L— is selected from:.Embodiment 112. A compound of formula (I) or a compound according to any one of Examples 1 to 104, or a pharmaceutically acceptable salt thereof, wherein W is selected from .Embodiment 113. A compound of formula (I), or a compound according to any one of Examples 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ Selected from C_1- C₄ Alkyl, C_1- C₃ Haloalkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, containing one or two heteroatoms independently selected from N, NH, NR¹⁷ , O or S as ring members, and containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring members of 4-6 membered heterocyclic ring, wherein each R¹⁰ Substituted with 1 to 5 groups independently selected from the following groups: C_1- C₄ Alkyl, deuterium, C_1- C₄ Halogen alkoxy, -OH, -CN, -OC(=O)R¹⁴ 、-L³ OR¹³ 、C_1- C₂ Halogenyl, pendoxyl, -halogen, -C_1- C₃ Alkoxy, -OC(=O)NR¹³ R¹⁴ 、-SO₂ R¹³ 、-SO₂ NR¹³ R¹⁴ 、-SO₂ NR¹³ C(=O)R¹³ 、-C(=O)NR¹³ SO₂ R¹³ 、-S(=O)R¹³ 、-S(=O)(=NR¹⁴ )R¹³ 、-NR¹³ SO₂ NR¹³ R¹⁴ 、-NR¹³ SO₂ R¹³ 、-NR¹³ R¹⁴ 、-NR¹⁴ C(=O)R¹³ 、-NR¹⁴ C(=O)OR¹³ 、-C(=O)NR¹³ R¹⁴ 、-C(=O)OR¹³ , -(a 4-7 membered heterocyclic group containing one or two heteroatoms independently selected from N, O or S as ring members), -C_3- C₅ Cycloalkyl and -(a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms including 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein the C_1- C₄ Alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclo, C_3- C₅ The cycloalkyl and 5-6 membered heteroaryl rings are each further substituted with 1 to 3 groups independently selected from the following groups: halogen, C_1- C₃ Alkyl, C_1- C₃ Halogen alkyl, -L⁴ OR¹³ 、-L⁴ CN and -L⁴ NR¹³ R¹⁴ .Embodiment 114. A compound of formula (I), or a compound according to any one of Examples 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ Selected from C_1- C₄ Alkyl, C_1- C₃ Haloalkyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, containing one or two heteroatoms independently selected from N, NH, NR¹⁷ , O or S as ring members, and containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring members of 4-6 membered heterocyclic ring, wherein each R¹⁰ Substituted with 1 to 5 groups independently selected from the following groups: C_1- C₄ Alkyl, deuterium, C_1- C₄ Halogen alkoxy, -OH, -CN, -OC(=O)R¹⁴ 、-L³ OR¹³ 、-NR¹³ R¹⁴ 、-NR¹⁴ C(=O)R¹³ 、-NR¹⁴ C(=O)OR¹³ 、-C(=O)NR¹³ R¹⁴ 、-C(=O)OR¹³ 、(containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S as a ring member of a 4-7 membered heterocycloalkyl group), -(containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S as a ring member of a 4-7 member heterocyclic group) and -C_3- C₅ Cycloalkyl, wherein the C_1- C₄ Alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocyclo and C_3- C₅ Cycloalkyl groups may be further substituted with 1 to 3 groups independently selected from the following groups: halogen, -OR¹³ 、-CN and -NR¹³ R¹⁴ .Embodiment 115. A compound of formula (I), or a compound according to any one of Examples 1 to 110, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isoxazolyl, oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, oxolinyl, piperidinyl, piperonyl, pyrrolidinyl and azocyclobutane, wherein each R¹⁰ Substituted with 1 to 4 groups independently selected from the following groups: methyl, ethyl, deuterium, -OCH₃ 、-OH、-OCHF₂ 、-CN、-NH₂ 、-NHCH₃ 、-N(CH₃ )₂ 、-NHR¹³ 、-NHCH(=O), -NHC(=O)CH₃ 、-NHC(=O)OCH₃ 、-NHC(=O)CH₂ NH₂ 、-NHC(=O)CH₂ N(CH₃ )₂ 、-NHC(=O)CH(CH₃ )NH₂ 、-NHC(=O)C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ OH, -OCH₂ CH(CH₃ )OH, -OCH₂ CH(CH₃ )₂ OH, -OCH(F)CH₂ OH, -OCF₂ CH₂ OH, -OCH₂ CH₂ NH₂ 、-OCH₂ CH(CH₃ )NH₂ 、-OCH₂ C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ NHCH₃ 、-OCH₂ CH₂ N(CH₃ )₂ 、-OCH(F)CH₂ NH₂ 、-OCF₂ CH₂ NH₂ 、-CH₂ OCH₂ CH₂ NH₂ 、-CH₂ CH₂ OH, -CH₂ OH, -CH₂ NH₂ 、-O-nitrocyclobutane、-C(=O)NH₂ 、-C(=O)NHCH₃ 、-OC(=O)CH₃ , cyclopropyl, azacyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl, wherein the methyl, ethyl, cyclopropyl, azacyclobutanyl, Pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl are each optionally further substituted with 1 to 3 groups independently selected from the following: F, -OH, -OCH₃ 、-NH₂ And methyl.Embodiment 116. A compound of formula (I), or a compound according to any one of Examples 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl, wherein each R¹⁰ Substituted with 1 to 4 groups independently selected from the following groups: methyl, ethyl, deuterium, -OCH₃ 、-OH、-OCHF₂ 、-CN、-NH₂ 、-NHCH₃ 、-N(CH₃ )₂ 、-NHR¹³ 、-NHCH(=O), -NHC(=O)CH₃ 、-NHC(=O)OCH₃ 、-NHC(=O)CH₂ NH₂ 、-NHC(=O)CH₂ N(CH₃ )₂ 、-NHC(=O)CH(CH₃ )NH₂ 、-NHC(=O)C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ OH, -OCH₂ CH(CH₃ )OH, -OCH₂ CH(CH₃ )₂ OH, -OCH(F)CH₂ OH, -OCF₂ CH₂ OH, -OCH₂ CH₂ NH₂ 、-OCH₂ CH(CH₃ )NH₂ 、-OCH₂ C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ NHCH₃ 、-OCH₂ CH₂ N(CH₃ )₂ 、-OCH(F)CH₂ NH₂ 、-OCF₂ CH₂ NH₂ 、-CH₂ OCH₂ CH₂ NH₂ 、-CH₂ CH₂ OH, -CH₂ OH, -CH₂ NH₂ 、-O-nitrocyclobutane、-C(=O)NH₂ 、-C(=O)NHCH₃ 、-OC(=O)CH₃ , cyclopropyl, azacyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl, wherein the methyl, ethyl, cyclopropyl, azacyclobutanyl, Pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl are each optionally further substituted with 1 to 3 groups independently selected from the following: F, -OH, -OCH₃ 、-NH₂ And methyl.Embodiment 117. A compound of formula (I), or a compound according to any one of Examples 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from cyclopropyl and cyclobutyl, wherein each R¹⁰ Substituted with 1 to 4 groups independently selected from the following groups: methyl, ethyl, deuterium, -OCH₃ 、-OH、-OCHF₂ 、-CN、-NH₂ 、-NHCH₃ 、-N(CH₃ )₂ 、-NHR¹³ 、-NHCH(=O), -NHC(=O)CH₃ 、-NHC(=O)OCH₃ 、-NHC(=O)CH₂ NH₂ 、-NHC(=O)CH₂ N(CH₃ )₂ 、-NHC(=O)CH(CH₃ )NH₂ 、-NHC(=O)C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ OH, -OCH₂ CH(CH₃ )OH, -OCH₂ CH(CH₃ )₂ OH, -OCH(F)CH₂ OH, -OCF₂ CH₂ OH, -OCH₂ CH₂ NH₂ 、-OCH₂ CH(CH₃ )NH₂ 、-OCH₂ C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ NHCH₃ 、-OCH₂ CH₂ N(CH₃ )₂ 、-OCH(F)CH₂ NH₂ 、-OCF₂ CH₂ NH₂ 、-CH₂ OCH₂ CH₂ NH₂ 、-CH₂ CH₂ OH, -CH₂ OH, -CH₂ NH₂ 、-O-nitrocyclobutane、-C(=O)NH₂ 、-C(=O)NHCH₃ 、-OC(=O)CH₃ , cyclopropyl, azacyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl, wherein the methyl, ethyl, cyclopropyl, azacyclobutanyl, Pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl are each optionally further substituted with 1 to 3 groups independently selected from the following: F, -OH, -OCH₃ 、-NH₂ And methyl.Embodiment 118. A compound of formula (I), or a compound according to any one of Examples 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from pyridyl, pyrazolyl and isoxazolyl; wherein each R¹⁰ Substituted with 1 to 4 groups independently selected from the following groups: methyl, ethyl, deuterium, -OCH₃ 、-OH、-OCHF₂ 、-CN、-NH₂ 、-NHCH₃ 、-N(CH₃ )₂ 、-NHR¹³ 、-NHCH(=O), -NHC(=O)CH₃ 、-NHC(=O)OCH₃ 、-NHC(=O)CH₂ NH₂ 、-NHC(=O)CH₂ N(CH₃ )₂ 、-NHC(=O)CH(CH₃ )NH₂ 、-NHC(=O)C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ OH, -OCH₂ CH(CH₃ )OH, -OCH₂ CH(CH₃ )₂ OH, -OCH(F)CH₂ OH, -OCF₂ CH₂ OH, -OCH₂ CH₂ NH₂ 、-OCH₂ CH(CH₃ )NH₂ 、-OCH₂ C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ NHCH₃ 、-OCH₂ CH₂ N(CH₃ )₂ 、-OCH(F)CH₂ NH₂ 、-OCF₂ CH₂ NH₂ 、-CH₂ OCH₂ CH₂ NH₂ 、-CH₂ CH₂ OH, -CH₂ OH, -CH₂ NH₂ 、-O-nitrocyclobutane、-C(=O)NH₂ 、-C(=O)NHCH₃ 、-OC(=O)CH₃ , cyclopropyl, azacyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl, wherein the methyl, ethyl, cyclopropyl, azacyclobutanyl, Pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl are each optionally further substituted with 1 to 3 groups independently selected from the following: F, -OH, -OCH₃ 、-NH₂ And methyl.Embodiment 119. A compound of formula (I), or a compound according to any one of Examples 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ is selected from oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, oxolinyl, piperidinyl, piperonyl, pyrrolidinyl and azocyclobutane, wherein each R¹⁰ Substituted with 1 to 4 groups independently selected from the following groups: methyl, ethyl, deuterium, -OCH₃ 、-OH、-OCHF₂ 、-CN、-NH₂ 、-NHCH₃ 、-N(CH₃ )₂ 、-NHR¹³ 、-NHCH(=O), -NHC(=O)CH₃ 、-NHC(=O)OCH₃ 、-NHC(=O)CH₂ NH₂ 、-NHC(=O)CH₂ N(CH₃ )₂ 、-NHC(=O)CH(CH₃ )NH₂ 、-NHC(=O)C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ OH, -OCH₂ CH(CH₃ )OH, -OCH₂ CH(CH₃ )₂ OH, -OCH(F)CH₂ OH, -OCF₂ CH₂ OH, -OCH₂ CH₂ NH₂ 、-OCH₂ CH(CH₃ )NH₂ 、-OCH₂ C(CH₃ )₂ NH₂ 、-OCH₂ CH₂ NHCH₃ 、-OCH₂ CH₂ N(CH₃ )₂ 、-OCH(F)CH₂ NH₂ 、-OCF₂ CH₂ NH₂ 、-CH₂ OCH₂ CH₂ NH₂ 、-CH₂ CH₂ OH, -CH₂ OH, -CH₂ NH₂ 、-O-nitrocyclobutane、-C(=O)NH₂ 、-C(=O)NHCH₃ 、-OC(=O)CH₃ , cyclopropyl, azacyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl, wherein the methyl, ethyl, cyclopropyl, azacyclobutanyl, Pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl are each optionally further substituted with 1 to 3 groups independently selected from the following: F, -OH, -OCH₃ 、-NH₂ And methyl.Embodiment 120. A compound of formula (I), or a compound according to any one of Examples 1 to 112, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ Selected from .Embodiment 121. A compound of formula (I), or a compound according to any one of Examples 1 to 120, or a pharmaceutically acceptable salt thereof, wherein R¹¹ and R¹² Each independently selected from H and methyl.Embodiment 122. A compound of formula (I), or a compound according to any one of Examples 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R¹³ Independently selected from H, C_1- C₄ Alkyl, containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 membered heterocycloalkyl, containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 member heterocyclic group and C_3- C₆ Cycloalkyl, wherein the C_1- C₄ Alkyl, heterocyclic and C_3- C₆ Cycloalkyl is optionally substituted with 1 to 3 groups independently selected from the following groups: C_1- C₄ Alkyl, halogen, -OH, -NR¹⁵ R¹⁶ 、-C(=O)OR¹⁵ 、C_1- C₂ Alkoxy and C substituted with 1 to 2 hydroxyl groups_1- C₄ Alkyl.Embodiment 123. A compound of formula (I), or a compound according to any one of Examples 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R¹³ Independently selected from H, C_1- C₄ Alkyl, containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 membered heterocycloalkyl, containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 member heterocyclic group and C_3- C₆ Cycloalkyl, wherein the C_1- C₄ Alkyl, heterocyclic and C_3- C₆ Cycloalkyl is optionally substituted with 1 to 3 groups independently selected from the following groups: C_1- C₄ Alkyl, halogen, -OH, -NR¹⁵ R¹⁶ 、-C(=O)OR¹⁵ and C substituted with 1 to 2 hydroxyl groups_1- C₄ Alkyl.Embodiment 124. A compound of formula (I), or a compound according to any one of Examples 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R¹³ Independently selected from H or C_1- C₄ Alkyl, where the C_1- C₄ The alkyl group is optionally substituted with 1 to 3 groups independently selected from the following groups: C_1- C₄ Alkyl, halogen, -OH, -NR¹⁵ R¹⁶ 、-C(=O)OR¹⁵ and C substituted with 1 to 2 hydroxyl groups_1- C₄ Alkyl.Embodiment 125. A compound of formula (I), or a compound according to any one of Examples 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R¹³ Independently selected from containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 membered heterocycloalkyl, containing 1 to 2 independently selected from N, NH, NR¹⁷ , O or S ring member 4-7 member heterocyclic group and C_3- C₆ Cycloalkyl, wherein the heterocyclic group and C_3- C₆ Cycloalkyl is optionally substituted with 1 to 3 groups independently selected from the following groups: C_1- C₄ Alkyl, halogen, -OH, -NR¹⁵ R¹⁶ 、-C(=O)OR¹⁵ and C substituted with 1 to 2 hydroxyl groups_1- C₄ Alkyl.Embodiment 126. A compound of formula (I), or a compound according to any one of Examples 1 to 121, or a pharmaceutically acceptable salt thereof, wherein each R¹³ Independently selected from H, methyl, -CHF₂ 、 .Embodiment 127. A compound of formula (I), or a compound according to any one of Examples 1 to 126, or a pharmaceutically acceptable salt thereof, wherein R¹⁴ Selected from H, C_1- C₄ Alkyl and C_3- C₆ Cycloalkyl, wherein the C_1- C₄ Alkyl and C_3- C₆ Cycloalkyl is optionally substituted with 1 to 3 groups independently selected from the following groups: C_1- C₄ Alkyl, halogen, -OH, -NR¹⁵ R¹⁶ 、C_1- C₂ Alkoxy and C substituted with 1 to 2 hydroxyl groups_1- C₄ Alkyl.Embodiment 128. A compound of formula (I), or a compound according to any one of Examples 1 to 126, or a pharmaceutically acceptable salt thereof, wherein R¹⁴ Selected from H and C_1- C₄ Alkyl.Embodiment 129. A compound of formula (I), or a compound according to any one of Examples 1 to 126, or a pharmaceutically acceptable salt thereof, wherein R¹⁴ It is H or methyl.Embodiment 130. A compound of formula (I), or a compound according to any one of Examples 1 to 130, or a pharmaceutically acceptable salt thereof, wherein R¹⁵ Selected from H and C_1- C₄ Alkyl.Embodiment 131. A compound of formula (I), or a compound according to any one of Examples 1 to 130, or a pharmaceutically acceptable salt thereof, wherein R¹⁵ It is H or methyl.Embodiment 132. A compound of formula (I), or a compound according to any one of Examples 1 to 131, or a pharmaceutically acceptable salt thereof, wherein R¹⁶ Selected from H and C_1- C₄ Alkyl.Embodiment 133. A compound of formula (I), or a compound according to any one of Examples 1 to 131, or a pharmaceutically acceptable salt thereof, wherein R¹⁶ It is H or methyl.Embodiment 134. A compound of formula (I), or a compound according to any one of Examples 1 to 133, or a pharmaceutically acceptable salt thereof, wherein L² For a key or direct link or branch link C_1- C₃ Alkyl group.Embodiment 135. A compound of formula (I), or a compound according to any one of Examples 1 to 133, or a pharmaceutically acceptable salt thereof, wherein L² One key, -CH₂ -or-CH₂ CH₂ -.Embodiment 136. A compound of formula (I), or a compound according to any one of Examples 1 to 133, or a pharmaceutically acceptable salt thereof, wherein L² for one key.Embodiment 137. A compound of formula (I), or a compound according to any one of Examples 1 to 136, or a pharmaceutically acceptable salt thereof, wherein L³ For a key or direct link or branch link C_1- C₃ Alkyl group.Embodiment 138. A compound of formula (I), or a compound according to any one of Examples 1 to 136, or a pharmaceutically acceptable salt thereof, wherein L³ One key, -CH₂ -or-CH₂ CH₂ -.Embodiment 139. A compound of formula (I), or a compound according to any one of Examples 1 to 136, or a pharmaceutically acceptable salt thereof, wherein L³ for one key.Embodiment 140. A compound of formula (I), or a compound according to any one of Examples 1 to 139, or a pharmaceutically acceptable salt thereof, wherein L⁴ For a key or direct link or branch link C_1- C₃ Alkyl group.Embodiment 141. A compound of formula (I), or a compound according to any one of Examples 1 to 139, or a pharmaceutically acceptable salt thereof, wherein L⁴ One key, -CH₂ -or-CH₂ CH₂ -.Embodiment 142. A compound of formula (I), or a compound according to any one of Examples 1 to 139, or a pharmaceutically acceptable salt thereof, wherein L⁴ for one key.Embodiment 143. A compound of formula (I), or according to any one of Examples 1 to 142, wherein when W is a ring which is optionally substituted, L may be C₁ -C₄ Straight or branched chain alkyl bond linking groups or a single bond.Embodiment 144. A compound of formula (I), or any one of Examples 1 to 142, wherein L is C₁ -C₄ Straight or branched chain alkyl linkage groups.Embodiment 145. A compound of formula (I), or any one of Examples 1 to 142, wherein L is -CH₂ -or-CH₂ CH₂ -.Embodiment 146. A compound of formula (I), or any one of Examples 1 to 142, wherein L is -CH₂ -.Embodiment 147. A compound of formula (I), or according to any one of embodiments 1 to 111, wherein when W is an optionally substituted ring, L is a bond.Embodiment 148. A compound of formula (I) having a structure of formula (II), or a pharmaceutically acceptable salt thereof,, W is the SO₂ R¹⁰ 、-SO₂ NR¹³ R¹⁴ or -SO₂ NR¹⁴ R¹⁰ Substituted cyclopropyl; R¹⁰ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropyl and pyridyl; wherein R¹⁰ Substituted with 1 to 4 groups independently selected from the following groups: methyl, ethyl, -OH, -NH₂ 、-CH₂ OH and -CH₂ NH₂ ; L is C₁ -C₄ Linear or branched alkyl bond linkage; R¹ Selected from H and C_1- C₃ Alkyl; R² is H; t is 0 and R³ Does not exist; R⁴ For H, C_1- C₃ Alkyl or C substituted with 1 to 2 groups independently selected from -OH and methyl_1- C₃ Alkyl; Each R¹³ and R¹⁴ Independently selected from H and C_1- C₄ Alkyl; and R^B 1 to 3 Rs depending on the situation⁵ phenyl group substituted; and each R⁵ Independently halogenated, -CN, C_1- C₃ Alkoxy or C_1- C₃ Alkyl.Embodiment 149. A compound of formula (I) having a structure of formula (II), or a pharmaceutically acceptable salt thereof,, W is the SO₂ R¹⁰ or -SO₂ NR¹⁴ R¹⁰ Substituted cyclopropyl; R¹⁰ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl and pyridyl; wherein R¹⁰ According to the situation, 1 to 2 independently selected from methyl, -OH, -NH₂ 、-CH₂ OH and -CH₂ NH₂ group substitution; L is -CH₂ -or-CH₂ CH₂ ; R¹ Selected from H and C_1- C₃ Alkyl; R² is H; t is 0 and R³ Does not exist; R⁴ For H, C_1- C₃ Alkyl or C substituted with 1 to 2 groups independently selected from -OH and methyl_1- C₃ Alkyl; R¹⁴ is H; and R^B Depending on the situation, 1 R⁵ phenyl group substituted; and R⁵ It is a halogen or -CN.Embodiment 150. A compound of formula (I) having a structure of formula (II), or a pharmaceutically acceptable salt thereof,, W is the SO₂ R¹⁰ or -SO₂ NR¹⁴ R¹⁰ Substituted cyclopropyl; R¹⁰ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl and pyridyl; wherein R¹⁰ According to the situation, 1 to 2 independently selected from methyl, -OH, -NH₂ 、-CH₂ OH and -CH₂ NH₂ group substitution; L is -CH₂ -; R¹ 、R² and R¹⁴ Each is H; t is 0 and R³ Does not exist; R⁴ For H, C_1- C₃ Alkyl or C substituted with 1 to 2 groups independently selected from -OH and methyl_1- C₃ Alkyl; and R^B Depending on the situation, 1 R⁵ phenyl group substituted; and R⁵ It is a halogen or -CN.Embodiment 151. A compound of formula (I), which is selected from any one of Examples 1-242, or a pharmaceutically acceptable salt thereof. This embodiment includes each embodiment described in the biological activity data table provided herein.Embodiment 152. The compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from:N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H -Pyrazolo[3,4-c ]pyridine-3-carboxamide; N-(4-cyanobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-N -(4-Fluorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-N ,1-dimethyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -((6-chloropyridin-3-yl)methyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-N -(4-Methylbenzyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; N-(4-cyano-3-fluorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -((5-chlorothien-2-yl)methyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyano-3-methylbenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyano-2-methylbenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyano-2-fluorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -((5-cyanopyridin-2-yl)methyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyano-3-methoxybenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(1-(4-cyanophenyl)ethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(1-(4-cyanophenyl)ethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(1-(4-chlorophenyl)-2-hydroxyethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(1-(4-chlorophenyl)-2-hydroxyethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(ethylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-Chlorobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyano-3-fluorobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]4-cyanobenzyl pyridine-3-carboxylate; 4-(2-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-oxoethoxy)benzonitrile; 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-oxoethoxy)benzonitrile;H -Pyrazolo[3,4-c ]pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)benzonitrile; 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)-1,2,4-oxadiazol-3-yl)methyl)benzonitrile; 4-((3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)benzonitrile; 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)-2H -tetrazol-2-yl)methyl)benzonitrile; 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)-1H- 4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1-H -Pyrazolo[3,4-c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; (R )- 4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H- Pyrazolo[3,4-c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; (S )-4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H- Pyrazolo[3,4-c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; 4-((3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)isoxazol-5-yl)methyl)benzonitrile; 4-((4-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)-1H -1,2,3-triazol-1-yl)methyl)benzonitrile; 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(1-((4,4-difluorocyclohexyl)methyl)-1H -1,2,3-triazol-4-yl)-1-methyl-5,6-dihydro-1H -Pyrazolo[3,4-c ]Pyridine-7(4H )-ketone;N -(4-chlorophenoxy)-1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (R)-N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (S)-N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;N -(4-Cyanobenzyl)-1-cyclopropyl-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 4-((8-((1-(methylsulfonyl)cyclopropyl)methyl)-1,7-dioxo-3,4,7,8,9,10-hexahydropyrido[3',4':3,4]pyrazolo[1,5-a ]Pyridine-2(1H )-yl)methyl)benzonitrile;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; N-(4-chlorobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;N -((6-chloropyridin-3-yl)methyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-Fluorobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(1-(4-cyanophenyl)ethyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(1-(4-cyanophenyl)ethyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)-1,1-d ₂ (1-(4-(2 ...H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; Acetic acid 2-((1-((3-((4-cyanobenzyl)aminocarboxyl)-1-methyl-7-oxo-4,5-dihydro-1H -Pyrazolo[3,4-c ]Pyridine-6(7H )-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropyl ester;N -(4-cyanobenzyl)-6-((1-((1-(difluoromethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((2-cyanopropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(3-fluoroaziridine cyclobutane-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-(N-oxolinyl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((1-(3-methoxypyrrolidin-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(3-hydroxyazinocyclobutane-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(3-methoxyazinocyclobutane-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-(2-oxa-6-azaspiro[3.3]heptane-6-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(3-hydroxypyrrolidin-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-((2-hydroxyethyl)amino)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-amino-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-carboxamido-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-acetamido-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (2-((1-((3-((4-cyanobenzyl)aminocarboxyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H -Pyrazolo[3,4-c ]6-((1-((1-(2-aminoacetamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-6-((1-((1-(2-aminopropionamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((1-(2-aminopropionamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(2-amino-2-methylpropionamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(2-(dimethylamino)acetamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(1,1-difluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(2-amino-1,1-difluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxy-2-methylpropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-((1-(2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(2-aminoethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(2-aminoethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridine-3-carboxamide; 6-((1-((1-(2-aminoethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-fluorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-((1-((1-((2-aminoethoxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-((2-aminoethoxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (R )-6-((1-((1-(2-aminopropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((1-(2-aminopropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-6-((1-((1-(2-aminopropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((1-(2-aminopropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-(2-(methylamino)ethoxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(Azocyclobutane-3-yloxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(2-amino-2-methylpropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 4-((4-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)-1H -1,2,3-triazol-1-yl)methyl)benzonitrile; 4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; (R )-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; (S )-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile; 6-((1-((1-amino-2-methyl-1-oxopropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-1-methyl-6-((1-((2-methyl-1-(methylamino)-1-oxopropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((2-hydroxy-2-methylpropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(((1s ,3s (3-Hydroxycyclobutyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(((1r ,3r (3-Hydroxycyclobutyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-Chlorobenzyl)-1-methyl-7-oxo-6-((1-aminosulfonylcyclopropyl)methyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (E )-N -(4-chlorobenzyl)-6-((1-(N -((dimethylamino) methyl) sulfonyl) cyclopropyl) methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(N ( ...H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(N-oxolinylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((4-hydroxypiperidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((3-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-((3-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((3-hydroxyazidocyclobutane-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N (cyclopropylaminosulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-((3-hydroxy-3-methylpyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((3-hydroxy-3-methylpyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(N -(((((((((((((((((((((((((((((((- ...-((-((-((-(-((-((-(-((-H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(piperidin-1-ylsulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-(N -(3-aminopropyl)sulfonylamine)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-(N -(2-aminoethyl)sulfonylamine)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-((4-methylpiperidin-1-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N -(piperidin-4-yl)sulfonylamine)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((4-aminopiperidin-1-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-(((3R ,4R )-3-amino-4-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-(((3S ,4S )-3-amino-4-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-6-((1-((3-aminopyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((3-aminopyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(N -(2-Hydroxyethyl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(N -(2-Hydroxyethyl)-N ( ...H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N -(2-Hydroxyethyl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N -(2-Hydroxyethyl)-N ( ...H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N -(1,3-dihydroxypropane-2-yl)-N ( ...H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(N -(1-Hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N -(1-Hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-((3-hydroxyazidocyclobutane-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-1-methyl-6-((1-(N ( ...H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(N -(2-Hydroxy-2-methylpropyl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(N -(1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(N -(1,3-dihydroxy-2-methylpropane-2-yl)-N ( ...H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N (2-(pyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(N -(1-methyl-1H -Pyrazol-3-yl)sulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(N -(6-methylpyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-1-methyl-7-oxo-6-((1-(N (2-(pyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N -(3-methoxypyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N -(3-methoxy-6-methylpyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(N -(2-methylpyridin-3-yl)sulfonylamine)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N -(2-methoxypyridin-3-yl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N -(6-methoxypyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(N -(3-methylpyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(N -(5-methylisoxazol-3-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-1-methyl-6-((1-(N -(5-methylisoxazol-3-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(N -(5-cyclopropylisoxazol-3-yl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-(oxacyclobutane-3-ylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((tetrahydro-2H -4-pyran-4-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((tetrahydrofuran-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((tetrahydrofuran-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-methyl-6-((1-((3-methyloxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((3-(hydroxymethyl)oxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((3-(aminomethyl)oxycyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(1-(4-chlorophenyl)ethyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(1-(4-chlorophenyl)ethyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1,3-dimethoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; N-(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (S )-N -(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-chlorobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-chlorobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-6-((1-((4-amino-3-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((4-amino-3-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((4-amino-3-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-6-((1-((4-amino-3-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-chlorobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-chlorobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-N -(4-chlorobenzyl)-6-((1-((4-(dimethylamino)-3-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-chlorobenzyl)-6-((1-((4-(dimethylamino)-3-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(2-amino-1-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((1-(2-amino-1-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (R )-6-((1-((4-amino-3-hydroxy-2,4-dimethylpentane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((4-amino-3-hydroxy-2,4-dimethylpentane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R)-6-((1-((3-amino-4-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (R )-6-((1-((3-amino-4-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-Chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide hydrochloride; ((1-((3-((4-chlorobenzyl)aminocarboxyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H -Pyrazolo[3,4-c ]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-D -Valine;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-(2-hydroxyethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-1-(2-hydroxyethyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; N-(4-chlorobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;N -(4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; 1-(2-(2-aminoethoxy)ethyl)-N-(4-chlorobenzyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R)-N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-oxobutyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-chlorobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(ethylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-((1-(hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; Ethylene glycol macrocycleN -(4-cyanobenzyl)formamide; ethylene glycol macrocycleN -(4-chlorobenzyl)formamide; Lactamide macrocycleN -(4-cyanobenzyl)formamide, and amine macrocyclesN -(4-cyanobenzyl)formamide.Embodiment 153. The compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from:N -(4-chlorobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (R )-6-((1-((4-amino-3-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; (S )-6-((1-((4-amino-3-hydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-(2-hydroxyethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; N-(4-chlorobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (R )-N -(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide;N -(4-cyanobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-((1-(hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide; andN -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N (2-(pyridin-2-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H -Pyrazolo[3,4-c ]Pyridine-3-carboxamide.Embodiment 154. The compound of formula (II) of any one of Examples 21 to 23, which has the structure of formula (IIa), or a pharmaceutically acceptable salt thereof: Among them, L and R¹ 、R² 、R^B 、R⁴ 、R¹⁰ 、R¹¹ and R¹² As defined for formula (I); or L, R¹ 、R² 、R^B 、R⁴ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 21; or L, R¹ 、R² 、R^B 、R⁴ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 22; or L, R¹ 、R² 、R^B 、R⁴ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 23.Embodiment 155. The compound of formula (II) of any one of Examples 21 to 23, which has the structure of formula (IIb), or a pharmaceutically acceptable salt thereof: Among them, L and R¹ 、R⁴ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined for formula (I); or L, R¹ 、R⁴ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 21; or L, R¹ 、R⁴ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 22; or L, R¹ 、R⁴ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 23.Embodiment 156. The compound of Example 155, or a pharmaceutically acceptable salt thereof, wherein R⁵ It is -CN or halogen.Embodiment 157. A compound of any one of Examples 154-156, or a pharmaceutically acceptable salt thereof, wherein R⁴ It is a methyl group.Embodiment 158. A compound of formula (IVa) having a structure of formula (IVd) Among them, L and R¹ 、R⁵ and R¹⁰ As defined for formula (I); or L, R¹ 、R⁵ and R¹⁰ As defined in Example 22; or L, R¹ 、R⁴ 、R⁵ 、R¹⁰ 、R¹¹ and R¹² As defined in Example 23.Embodiment 159. The compound of Example 158, or a pharmaceutically acceptable salt thereof, wherein R⁵ It is -CN or halogen.Embodiment 160. The compound of formula (Vc) of Example 30, or a pharmaceutically acceptable salt thereof, wherein each R⁵ is a halogenated group, and R¹⁰ For two -L³ OH substituted C_1- C₅ Alkyl, where L³ As defined in formula (I).Embodiment 161. The compound of formula (Va) of Example 30, or a pharmaceutically acceptable salt thereof, wherein R⁵ is a halogenated group, and R¹⁰ For two -L³ OH substituted C_1- C₅ Alkyl, where L³ As defined in formula (I).Embodiment 162. The compound of formula (Va) of Example 30, or a pharmaceutically acceptable salt thereof, wherein R⁵ is -CN, and R¹⁰ For two -L³ OH substituted C_1- C₅ Alkyl, where L³ As defined in formula (I).Embodiment 163. A compound of formula (I) having a structure of formula (VIII), or a pharmaceutically acceptable salt thereof, Among them, R¹⁰ is selected from: phenyl, unsubstituted or substituted with one -CN; unsubstituted or substituted with one selected from -L³ Halogen, -L³ OH or -L³ NHC(=O)R¹³ A 6-membered heteroaryl group having 1-2 heteroatoms substituted by a radical, each heteroatom being N, wherein L³ For a key or direct link or branch link C₁ -C₃ Alkyl group, and R¹³ For C₁ -C₄ Alkyl; and through a -L³ C(=O)NR13R14 or 2 or 3 -L³ OH substituted C₁ -C₅ Alkyl, where L³ For a key or direct link or branch link C₁ -C₃ Alkylene, R¹³ H or C₁ -C₄ Alkyl, and R¹⁴ H or C₁ -C₄ Alkyl.Embodiment 164. The compound of Example 163, or a pharmaceutically acceptable salt thereof, wherein L³ for one key.Embodiment 165. The compound of Example 163 or 164, or a pharmaceutically acceptable salt thereof, wherein R¹⁰ It is an unsubstituted 6-membered heteroaryl group having 1-2 heteroatoms, each heteroatom being N.Embodiment 166. A compound of any one of Examples 163-165, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: N-(4-cyanobenzyl)-6-((1-(N-(6-(hydroxymethyl)pyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-((1-(N-(6-acetamidopyridin-2-yl)sulfonylamine)cyclopropyl )methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyridine-2-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyridine-2-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; Oxy-6-((1-(N-phenylsulfonylamine)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-6-((1-(N-(3-fluoropyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-6-((1-(N-(3-fluoropyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; ((N-(2-cyanophenyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (R )-N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; (S )-N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide 6-((1-(N-(4-amino-2-methyl-4-oxobutane-2-yl)sulfonamido)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; 6-((1-(N-(4-amino-2-methyl-4-oxobutane-2-yl)sulfonamido)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3 ,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-6-((1-(N-(3-(dimethylamino)-3-oxopropyl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-6-((1-(((3S,4S)-3 ,4-dihydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(1-(oxadiazol-3-yl)cyclopropyl)aminesulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide); H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-6-((1-(N-(1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-1-methyl-7-oxo- 6-((1-(N-(pyrimidin-2-ylmethyl)sulfonylamine)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(1-(pyrimidin-2-ylmethyl)sulfonylamine)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(1-(pyrimidin-2-ylmethyl)sulfonylamine)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide pyridine-3-carboxamide; N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyridine-2-ylmethyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide; N-(4-cyanobenzyl)-6-((1-(N-(1,3-dihydroxy-2-(hydroxy =N-(4-((1-( ...Embodiment 167. A compound of any one of Examples 1-150, or a pharmaceutically acceptable salt thereof, wherein R⁴ 1 to 2 independently selected from -OH and R¹⁰ C substituted with a group₂ -C₃ Alkyl.Embodiment 168. A compound as claimed in any one of claims 1-150 and 167, or a pharmaceutically acceptable salt thereof, wherein R⁴ Substituted with -OH and optionally substituted with methyl.Embodiment 169. A compound as claimed in any one of claims 1-150 and 167-168, or a pharmaceutically acceptable salt thereof, wherein W is L² SO2R¹⁰ .Embodiment 170. A compound as claimed in any one of claims 1-150 and 167-169, or a pharmaceutically acceptable salt thereof, wherein L² is a key and R¹⁰ For 1-3 selected from C₁ -C₄ C substituted with alkyl and -OH groups₁ -C₄ Alkyl.

Compounds of formula (VII) are novel and useful as intermediates for preparing compounds of formula (I)-(VI) described herein.

The compounds of formula (VII) are novel and suitable intermediates for preparing the compounds of formula (VIII) described herein. General Synthesis Procedure

The compounds of the present invention can be produced by organic synthesis methods known to those skilled in the art with reference to the following general synthesis schemes and in more detail in the examples.

All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts used to synthesize the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those of ordinary skill in the art (Houben-Weyl 4th edition 1952, Methods of Organic Synthesis, Thieme, Vol. 21).

In the context of this document, unless the context indicates otherwise, a readily removable group that is not a component of the specific desired end product of the compounds of the present invention is termed a "protecting group." The protection of functional groups by such protecting groups, the protecting groups themselves and their cleavage reactions are described, for example, in standard reference works such as: Science of Synthesis: Houben-Weyl Methods of Molecular Transformation. Georg Thieme Verlag, Stuttgart, Germany. 2005. 41627 pages (URL: http://www.science-of-synthesis.com (Electronic Version, 48 volumes)); J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", 3rd edition, Wiley, New York 1999; "The Peptides", Vol. 3 (Editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981; "Methoden der Organischen Chemie" (Methods of Organic Chemistry), Houben Weyl, 4th edition, volume 15/I, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jeschkeit, "Aminosäuren, Peptide, Proteine" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974. A characteristic of a protecting group is that it is readily removable (ie, does not cause undesirable side reactions), for example, by solvent degradation, reduction, photolysis, or under physiological conditions (eg, by enzymatic cleavage).

General methods for synthesizing compounds of formula (I) are provided below in Schemes I-VI. In particular, Schemes I to III show General Methods 1 to 14 for synthesizing compounds of formula (I) wherein Z is W and LMC is absent, and wherein ^R1 , ^R2 , ^R3 , R4, ^R15 , ^RB , t, L and W are as defined herein for ^compounds of formula (I). Scheme I

Scheme 1 shows general methods 1 to 7 for synthesizing compounds of formula (I) wherein X is , and Y is a key, Bicyclic intermediates such as intermediate 1-1 may be alkylated on the N to attach the WL-moiety of interest, for example where L is attached via _-CH2- . _WLX1 represents an alkylating agent suitable for such reactions, wherein _X1 is a leaving group such as a halogen group such as Br or I or a sulfonate leaving group such as mesylate, tosylate or triflate. The WL-moiety may of course contain functional groups which may be further modified in the product of formula (I), such as hydroxyl or amine groups, preferably in protected form, which may be deprotected and further derivatized.

^RC can be a simple alkyl ester such as methyl, ethyl, propyl, isopropyl, tert-butyl or n-butyl; and if WL- contains an ester, ^RC can be a different ester such as a benzyl group that is easily distinguishable from the benzyl group in WL-, so that ^RC can be selectively hydrolyzed for coupling in Scheme I. In some embodiments, ^{RC is} an ester that hydrolyzes under alkylation reaction conditions, possibly due to the presence of adventitious moisture or hydroxide; in other embodiments, a separate hydrolysis step is used, such as the addition of lithium hydroxide, sodium hydroxide or potassium hydroxide and water. The resulting free carboxylate compound is then readily coupled with a suitable amine containing the desired ^RB group using standard amide bond forming conditions and suitable reagents. This can be a direct amidation of a carboxylic acid ester (Methods 1 and 2), or it can be achieved by converting a carboxylic acid into an activated intermediate (acyl chloride, acyl anhydride, etc.) (Method 4), as known in the art and illustrated by the accompanying examples. Examples of amide coupling agents used in Methods 1, 2, 4, and 5 include, but are not limited to, EDCI, HATU, HBTU, TBTU, and T3P. In addition, a carboxylic acid can be converted into an activated intermediate (Method 5) and then etherified. Typical etherifications are carried out using alkyl halides (Cl, Br, I) in the presence of a base such as _KCO3 or KOH.

Alternatively, the carboxylic acid is esterified using Lewis acid or Brønstedt acid catalyzed esterification of the carboxylic acid with an alcohol (Method 6), however, examples of other esterification reagents include diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), di-tert-butyl azodicarboxylate (DTBAD), dicyclohexylcarbodiimide (DCC)/4-N,N-dimethylaminopyridine (DMAP) and 2,4,6-trichlorobenzyl chloride/4-N,N-dimethylaminopyridine (DMAP).

Finally, for compounds of formula (I) where ^R4 is H and ^R15 contains an alkylhalide moiety, the diamine on the pyrazole ring can be alkylated (Method 7), thereby forming a third fused ring. Alternatively, when ^R15 contains a suitable reactive group, hydroamination with an alcohol and amine alkylation can be used. Scheme II

Scheme II shows a general method for synthesizing compounds of formula (I) wherein X is a 5-6 membered heteroaryl group and Y is . Using the carboxylic acid intermediate described in process (I), the compound of formula (I) containing oxadiazole can be easily obtained. In method 8, oxadiazole is synthesized by condensation with a carboxylic acid, followed by dehydration and cyclization of the resulting diacylhydrazine intermediate. Alternatively, in method 9, oxadiazole is synthesized by condensation of a carboxylic acid and an amide oxime, followed by cyclization. Finally, in method 10, the carboxylic acid intermediate is converted to an amide, followed by formation of a nitrile, which is then used to form an amine oxime intermediate. Then, oxadiazole is formed by condensation of a carboxylic acid and an amide oxime, followed by cyclization. The reagents used in such methods are known in the art and are illustrated by the accompanying examples. Process III

Scheme III shows a general method for synthesizing compounds of formula (I) wherein X is a 5-6 membered heteroaryl or a 5-6 membered heterocyclic group, and Y is a bond or . Using the carboxylic acid intermediate or the corresponding ester intermediate described in process (I), a compound of formula (I) containing triazole, tetrazole, isothiocyanate or dihydroisothiocyanate is obtained. In method 11, the aldehyde intermediate formed from the ester is used to form a nitrile intermediate. The nitrile intermediate and the azide intermediate are then subjected to copper-catalyzed "click" chemistry to form the triazole. In addition, in method 12, the aldehyde intermediate formed from the ester is used to form an oxime intermediate, which is then converted into a chlorinated formimide derivative. The chlorinated formimide derivative reacts with an alkene to produce a dihydroisothiocyanate. Alternatively, the chlorinated formimide derivative reacts with a nitrile intermediate (method 13) to obtain an isothiocyanate. Finally, in method 14, the carboxylic acid intermediate is converted to the amide, followed by the nitrile, followed by the tetrazole intermediate, which is then alkylated on the N using an alkyl halide.

Scheme IV shows a general method for synthesizing compounds of formula (I) wherein LMC is present and wherein ^R1 , ^R2 , ^R3 , ^R4 , ^R15 , ^RB , t and L are as defined herein for compounds of formula (I). Scheme IV

In Scheme (IV), the amine protected bicyclic intermediate described in Scheme (I), such as intermediate 1-1, is used to obtain the macrocyclic compound of formula (I). Here the bicyclic intermediate can be alkylated on N as described in Scheme I to attach the OH-ZL- moiety of interest, for example wherein L is attached via _-CH2- . The hydroxyl group of the OH-ZL group is alkylated, thereby attaching the linking moiety, which is further attached by alkylation of the deprotected amine on N following deprotection of the amine. The ester is converted to the corresponding carboxylic acid, followed by acylation using the desired amine intermediate.

Scheme V shows a general method for the synthesis of compounds of formula (I) wherein LMC is present and wherein ^R1 , ^R2 , ^R3 , ^R4 , ^R15 , ^RB , t and L are as defined herein for compounds of formula (I). Scheme V

In Scheme (V), the amine protected bicyclic intermediate described in Scheme (I), such as intermediate 1-1, is used to obtain the macrocyclic compound of formula (I). Here the bicyclic intermediate can be alkylated on the N as described in Scheme I to attach the OH-ZL- moiety of interest, especially where L is attached via _-CH2- . The ester is then converted to the corresponding carboxylic acid followed by amidation with the desired amine intermediate. After removal of the protecting group, the amine is alkylated to attach the linking group, which is then activated with an azide moiety. The hydroxyl group of the OH-ZL group is converted to a carboxylic acid, followed by amidation via the azide moiety, thereby attaching the linking group and allowing the macrocycle to form.

Scheme VI shows a general method for the synthesis of compounds of formula (I) wherein LMC is present and wherein ^R1 , ^R2 , ^R3 , ^R4 , ^R15 , ^RB , t and L are as defined herein for compounds of formula (I). Scheme VI

In Scheme (VI), the amine protected bicyclic intermediate described in Scheme (I), such as intermediate 1-1, is used to obtain the macrocyclic compound of formula (I). Here the bicyclic intermediate can be alkylated on the N as described in Scheme I to attach the OH-ZL- moiety of interest, for example wherein L is attached via _-CH2- . The ester is then converted to the corresponding carboxylic acid followed by amidation with the desired amine intermediate. After removal of the protecting group, the amine is alkylated to attach the linking group, which is then activated with an azide moiety. The hydroxyl group of the OH-ZL group is converted to an aldehyde, which is then amidated via the azide moiety, thereby attaching the linking group and allowing the macrocycle to form.

Although Schemes IV-VI are shown for the synthesis of And Y is a key, The general method for preparing macrocyclic compounds of formula (I) is as follows, but such method can be applied to macrocyclic compounds wherein X is , , 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl or 5-6 membered heterocyclo and Y is a bond, Embodiments thereof.

A person skilled in the art can readily prepare a variety of compounds of formula (I)-(VI) using the above methods as well as other extensions, modifications and variations as illustrated by the following examples.

The intermediates and final products can be worked up and/or purified according to suitable methods, for example using chromatography, distribution methods, (re)crystallization and the like.

Depending on the choice of starting materials and procedures, the compounds may exist in the form of one of the possible isomers or in the form of a mixture thereof, for example in the form of pure optical isomers or in the form of isomer mixtures, such as racemates and diastereomeric mixtures, depending on the number of asymmetric carbon atoms. The present invention is intended to include all such possible stereoisomers, including racemic mixtures, diastereomeric mixtures and optically pure forms. Optically active (R)- and (S)-isomers can be prepared using chiral synthetic components or chiral reagents, or resolved using known techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl group, the cycloalkyl substituents may have a cis or trans configuration. All tautomeric isomeric forms are also intended to be included.

Any resulting isomeric mixtures can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric or optical isomers or diastereomers, for example, by analysis and/or fractional crystallization.

The mixtures of isomers obtainable according to the invention can be separated in a manner known per se into the individual isomers; diastereomers can be separated, for example, by distribution between heterogeneous solvent mixtures, recrystallization and/or chromatography separation (for example over silica gel) or by medium-pressure liquid chromatography, for example over reversed-phase columns; and racemates can be separated, for example, by salt formation with optically pure salifying reagents and separation of the diastereoisomer mixtures thus obtainable, for example, by fractional crystallization or by chromatography over optically active column materials.

Any resulting racemate of the final product or intermediate can be resolved into the optical antipodes by known methods, for example by separation of its diastereomeric salt obtained with an optically active acid or base and liberating the optically active acidic or basic compound. In particular, the alkaline moiety can thus be used to resolve the compounds of the invention into their optical antipodes, for example by fractional crystallization of salts formed from optically active acids such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, apple acid or camphor-10-sulfonic acid. The racemic product can also be resolved by chiral chromatography, for example high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Various compounds of the present invention contain one or more chiral centers. Such compounds can be made and used as single isomers or mixtures of isomers. Methods for separating isomers (including diastereomers and enantiomers) are known in the art, and examples of suitable methods are described herein. In certain embodiments, the compounds of the present invention are used as substantially pure single isomers, meaning that at least 90% of the compound sample is a specified isomer and less than 10% of the sample is any other isomer or mixture of isomers. For example, at least 95% of the sample is a single isomer. In view of the present disclosure, the selection of suitable isomers is within the normal skill level. For example, one isomer is more active in the in vitro analysis of herpes virus DNA polymerase described herein. Where the difference in in vitro activity between isomers is relatively small, e.g., less than about 4-fold, individual isomers can be selected based on the degree of activity against viral replication in cell culture using methods such as those described herein: for example, an isomer with a lower _IC50 or _EC50 can be selected.

In addition, the compounds of the present invention (including their salts) can also be obtained in the form of their hydrates, or include other solvents used for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water); therefore, the present invention is intended to cover both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salt) and one or more solvent molecules. These solvent molecules are those solvent molecules commonly used in medical technology that are known to be harmless to the recipient, such as water, ethanol and the like. The term "hydrate" refers to a complex in which the solvent molecule is water.

The compounds of the present invention, including their salts, co-crystals, hydrates and solvates, may inherently or by design form polymorphs.

As used herein, the term "salt" refers to an acid addition salt or a base addition salt of the compounds of the present invention. "Salts" include, in particular, "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological utility and properties of the compounds of the present invention and are generally not biologically or otherwise desirable. In many cases, the compounds of the present invention are capable of forming acid salts and/or base salts by virtue of the presence of amine and/or carboxyl groups or similar groups thereof.

Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronide, hippurate, hydroiodide/iodine. , hydroxyethanesulfonate, lactate, lactobionate, lauryl sulfate, apple acid salt, cis-butenedioate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthoate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, dihydroxynaphthoate, phosphate/hydrogenphosphate/dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluenesulfonate and trifluoroacetate.

Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid and the like. Pharmaceutically acceptable base addition salts can be formed from inorganic bases and organic bases.

Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from rows I to XII of the Periodic Table of the Elements. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

Organic bases from which salts can be derived include, for example, primary, diamines, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; base ion exchange resins and the like. Certain organic amines include isopropylamine, benzathine, cholate, diethanolamine, diethylamine, lysine, meglumine, piperidine, and sulfadiazine.

The pharmaceutically acceptable salts of the present invention can be synthesized from the alkaline or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid forms of such compounds with a stoichiometric amount of an appropriate base (such as a hydroxide, carbonate, bicarbonate or the like of Na, Ca, Mg or K), or by reacting the free base forms of such compounds with a stoichiometric amount of an appropriate acid. Such reactions are usually carried out in water or an organic solvent, or in a mixture of the two. Usually, when practicable, a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile is used. Lists of other suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences", 20th edition, Mack Publishing Company, Easton, Pa., (1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

Salts of the compounds of the invention having at least one salt-forming group can be prepared in a manner known per se. For example, salts of the compounds of the invention having an acid group can be formed, for example, by treating the compound with a metal compound, such as an alkali metal salt of a suitable organic carboxylic acid, for example the sodium salt of 2-ethylhexanoic acid, with an organic alkali metal or alkaline earth metal compound, such as the corresponding hydroxides, carbonates or bicarbonates, such as the hydroxides, carbonates or bicarbonates of sodium or potassium, with a corresponding calcium compound or with ammonia or a suitable organic amine, using a stoichiometric amount or only a small excess of the salt-forming agent. Acid addition salts of the compounds of the invention are obtained in the usual manner, for example by treating the compound with an acid or a suitable anion exchange reagent. Internal salts of compounds of the invention containing acid and base salt forming groups (e.g. free carboxyl groups and free amine groups) can be formed, for example, by neutralizing a salt (e.g. an acid addition salt) to the isoelectric point, for example with a weak base, or by treating with an ion exchange agent.

Salts may be converted into the free compounds in the usual manner; metal and ammonium salts may be converted, for example, by treatment with a suitable acid, and acid addition salts by treatment with a suitable alkaline reagent.

Any formula given herein is intended to represent unlabeled forms of the compounds of the invention as well as isotopically labeled forms of the compounds of the invention having up to three atoms with non-natural isotopic distributions, such as deuterium-enriched or ¹³ C or ¹⁵ N sites. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced with atoms having selected atomic masses or mass numbers other than the natural abundance mass distribution. Examples of isotopes that may be beneficially incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F, ³¹ P, ³² P, ³⁵ S, ³⁶ Cl, ¹²⁵ I, respectively. The present invention includes various isotopically labeled compounds of the present invention, for example, compounds of the present invention labeled with radioactive isotopes (such as ³ H and ¹⁴ C) or non-radioactive isotopes (such as ² H and ¹³ C) present at levels substantially above the normal isotopic distribution. Such isotopically labeled compounds are useful in metabolic studies (using, for example, ¹⁴ C); reaction kinetic studies (using, for example, ² H or ³ H); detection or imaging techniques, such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including analysis of drug or substrate tissue distribution; or for radiotherapy of patients. In particular, compounds of the present invention labeled with ¹⁸ F may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the invention can generally be prepared by techniques known to those skilled in the art or by methods analogous to those described in the accompanying Examples and Preparations, using appropriate isotopically labeled reagents in place of the unlabeled reagents normally used. Labeled samples may be suitable for very low isotope incorporation, such as when radiolabeling is used to detect trace amounts of a compound.

Furthermore, substitution with heavier isotopes more generally, particularly deuterium (i.e., ² H or D), can afford certain therapeutic advantages resulting from greater metabolic stability, such as prolonged in vivo half-life or reduced dosage requirements or improved therapeutic index. It will be understood that deuterium is considered in this context as a substituent of the compounds of the invention, and that samples of compounds having deuterium as a substituent typically have at least 50% deuterium incorporation at the labeled position. The concentration of such heavier isotopes, particularly deuterium, can be defined by an isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" means the ratio between the isotopic abundance and the natural abundance of a specified isotope. If a substituent in a compound of the invention is designated as deuterium, the compound has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation).

Pharmaceutically acceptable solvent compositions according to the present invention include those wherein the crystallization solvent may be isotopically substituted, for example _D2O , ^d6 -acetone, ^d6 -DMSO.

The compounds of the present invention containing groups capable of acting as donors and/or acceptors of hydrogen bonds are capable of forming co-crystals with suitable co-crystal formers. Such co-crystals can be prepared from the compounds of the present invention by known co-crystal formation procedures. Such procedures include grinding, heating, co-subliming, co-melting or contacting the compounds of the present invention and the co-crystal formers in a solution under crystallization conditions, and isolating the co-crystals thus formed. Suitable co-crystal formers include the co-crystal formers described in WO 2004/078163. Therefore, the present invention further provides co-crystals comprising the compounds of the present invention.

Unless otherwise indicated herein or clearly contradicted by context, all methods described herein can be performed in any suitable order. The use of any and all examples or exemplary language (such as "such as") provided herein is intended only to better illustrate the present invention and does not limit the scope of the present invention otherwise claimed.

The present invention also provides methods for preparing compounds of formula (I) as described herein and intermediates suitable for preparing compounds of formula (I). Therefore, the present invention also includes a method for preparing a compound of formula (I), comprising: wherein: X ₁ represents -OH or a leaving group; t is 0, 1 or 2; each R ^3, when present, is a substituent on the ring to which -LW is directly attached, wherein each R ³ is independently selected from halogen, CN, C _1- C ₃ alkoxy, C _1- C ₃ alkyl, C(=O)OR ¹⁰ and C(=O)NR ¹³ R ¹⁴ ; R ⁴ is H, C _1- C ₃ alkyl, C _3- C ₆ cycloalkyl or C _1- C ₃ alkyl substituted with 1 to 2 groups independently selected from -OH, -C(=O)R ¹⁵ and R ¹⁰ ; L is a C _1- C ₄ straight or branched chain alkyl bond linking group or a single bond; W is H, -OH, -OR ¹⁰ , -C(=O)NR ¹³ R ¹⁴ , -C(=O)OR ¹³ , -NR ¹³ R ¹⁴ , -NR ¹³ C(=O)OR ¹⁰ , -NR ¹³ C(=O)R ¹⁰ , -SO ₂ R ¹⁰ , -SO ₂ NR ¹³ R ¹⁴ , -NR ¹³ SO ₂ R ¹⁰ , -P(=O)(OR ¹³ ) ₂ , -S(=O)R ¹⁰ , -S(=O)(=NR ¹³ )R ¹⁰ , -CR ¹¹ R ¹² C(=O)NR ¹³ R ¹⁴ , -CR ¹¹ R ¹² C(=O)OR ¹³ , -CR ¹¹ R ¹² NR ¹³ R ¹⁴ , -CR ¹¹ R ¹² NR ¹³ C(=O)OR ¹⁰ , -CR ¹¹ R ¹² NR ¹³ C(=O)R ¹⁰ , -CR ¹¹ R ¹² SO ₂ R ¹⁰ , -CR ¹¹ R ¹² SO ₂ NR ¹³ R ¹⁴ , -CR ¹¹ R ¹² NR ¹³ SO ₂ R ¹⁰ , -CR ¹¹ R ¹² P(=O)(OR ¹³ ) ₂ , -CR ¹¹ R ¹² S(=O)R ¹⁰ , -CR ¹¹ R ¹² S(=O)(=NR ¹³ )R ¹⁰ , 3-6 membered cycloalkyl, phenyl, 5-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S, containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S as ring members, or a 5-membered heteroaryl group which is optionally fused to a phenyl group and has 1 to 4 heteroatoms selected from N, O and S as ring members, wherein the 3-6 membered cycloalkyl group, phenyl group, 5-6 membered heterocycloalkyl group, 5-6 membered heterocycloalkyl group and 5-membered heteroaryl group of W are each optionally substituted with 1 to 3 groups independently selected from the following groups: C _1- C ₃ alkyl group, oxo group, halogen group, C _1- C ₃ halogenalkyl group, -L ² OH, -L ² OR ¹⁰ , -L ² OC(═O)NR ¹³ R ¹⁴ , -L ² SO ₂ R ¹⁰ , -L ² SO ₂ NR ¹⁴ R ¹⁰ , -L ² SO ₂ NR ¹³ R ¹⁴ , -L ² SO ₂ N=CR ¹³ NR ¹³ R ¹⁴ , -L ² SO ₂ NR ¹³ C(=O)R ¹⁰ , -L ² C(=O)NR ¹³ SO ₂ R ¹⁰ , -L ² S(=O)R ¹⁰ , -L ² S(=O)(=NR ¹³ )R ¹⁰ , -L ² NR ¹³ SO ₂ NR ¹³ R ¹⁴ , -L ² NR ¹³ SO ₂ R ¹⁰ , -L ² NR ¹³ R ¹⁴ , -L ² NR ¹³ C(=O)R ¹³ , -L ² NR ¹³ C(=O)OR ¹⁰ , -L ² C(=O)NR ¹³ R ¹⁴ and -L ² C(=O)OR ¹³ ; R ^{R 10} is independently selected at each occurrence from C _1- C ₄ alkyl, C _1- C ₃ halogenalkyl, 3-6 membered cycloalkyl, phenyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, 4-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S, and 4-6 membered heterocyclo containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, wherein each R ¹⁰ is optionally substituted with 1 to 5 groups independently selected from the following: C _1- C ₄ alkyl, deuterium, C _1- C ₄ halogenalkyl, -L ³ OH, -L ³ CN, -L ³ OC(═O)R -L ³ OR ¹³ , C _{1 -} C ₂ halogenalkyl, oxo, -L ³ halogen, -L ^{3 C} _{1 -} C ₃ alkoxy, -L ³ OC(═O)NR ¹³ R ¹⁴ , -L ³ SO ₂ R ¹³ , -L ³ SO ₂ NR ¹³ R ¹⁴ , -L ³ SO ₂ NR ¹³ C(═O)R ¹³ , -L ³ C(═O)NR ¹³ SO ₂ R ¹³ , -L ³ S(═O)R ¹³ , -L ³ S(═O)(═NR ¹⁴ )R ¹³ , -L ³ NR ¹³ SO ₂ NR ¹³ R ¹⁴ , -L ³ NR ¹³ SO ₂ R ¹³ , -L ³ NR ¹³ R ¹⁴ , -L -L ³ -( ^4-7 membered heterocycloalkyl containing 1 ^{to 2} ring members independently ^selected from N, NH ^, NR ¹⁷ , O or S), -L ³ -( ^4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S), -L 3 -C ^3- C 5 ^cycloalkyl and -L 3 -( ^4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR 17 , O or S), -L 3 -C 3- C 5 cycloalkyl and -L ³ -(4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S), -L 3 -(4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR 17 , O or S), -L ³ -C _3- C ₅ cycloalkyl and -L ³ -(having 1 to 4 heteroatoms including 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members) wherein the C1 _{- C4} alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl, C3 _{- C5} cycloalkyl and 5-6 membered heteroaryl ring are each optionally further substituted with 1 to 3 groups independently selected from the following: halogen, C1 _{- C3} alkyl, C1 _{- C3} ^halogenalkyl , ^-L4OR13 , ^-L4CN and ^-L4NR13R14 ; ^R11 and ^{R12 are each} independently selected from H and C1 _{- C4} alkyl; each ^R13 is independently selected from H, _C1- C The present invention relates to a _C1-C4 alkyl group, a 4-7 membered heterocycloalkyl group containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, a 4-7 membered heterocycloalkyl group containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, and a C _{3 -} C ₆ cycloalkyl group, wherein the C _{1 -} C ₄ alkyl group, the heterocycloalkyl group and the C _{3 -} C ₆ cycloalkyl group are optionally substituted with 1 to 3 groups independently selected from the following: C _{1 -} C ₄ alkyl group, a halogen group, -OH, -NR ¹⁵ R ¹⁶ , -C (= O) OR ¹⁵ , a C _{1 -} C ₂ alkoxy group and a C _{1 -} C ₄ alkyl group substituted with 1 to 2 hydroxyl groups; R ¹⁴ is selected from H, C _{1 -} C ₄ alkyl group and C ₃ - C 6 wherein the C1 _{- C4} alkyl and C3 _{- C6} ^cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C1 _{- C4} alkyl, halogen, -OH, ^-NR15R16 , C1 _{- C2} alkoxy and C1 _{- C4} alkyl substituted with 1 to ₂ hydroxyl groups; or ^R13 and ^R14 together with the nitrogen atom to which both are directly attached may form a 4-6 membered ring optionally containing additional N, O or S as ring members and optionally substituted with one to three groups selected from C1 _{- C2} alkyl, C1 _{- C2} alkoxy, pendoxy and hydroxyl groups; each of ^L2 , ^L3 and ^L4 is independently a bond or a straight chain or branched chain C1 _- C ₃ alkylene groups, and ' represents a single bond or a double bond; and the compound of formula (I-2): wherein: ^RB is phenyl, pyridyl, thienyl, pyrimidinyl or 5-8 membered cycloalkyl, wherein ^RB is optionally substituted by 1 to 3 ^R5 groups; ^R1 is selected from H, C1 _{- C3} alkyl and C1 _{- C3} alkyl substituted by 1 to 3 -OH groups; ^R2 is selected from H, C1 _{- C3} alkyl and C1 _{- C3} alkyl substituted by 1 to 3 -OH groups; or ^R1 and ^R2 together with the carbon to which they are attached can form a 3-6 membered cycloalkyl ring; each ^R5 is independently selected from halogen, -CN, ^hydroxyl , ^-NR13R14 , C3 _{- C6} cycloalkyl, C1 _{- C3} alkoxy, C1- _C3 halogenalkyl and _{C1 -} C6 alkyl substituted by 1 to 3 ^R6 groups. wherein when _RB is substituted ^with two ^R5 and each ^R5 is a C1 _{- C3} ^alkyl group optionally substituted with 1 to 3 R6 groups, when directly attached to the same carbon atom, together with the carbon to which the two are directly attached, they may form a 3-5 membered cycloalkyl ring optionally substituted with 1 to 3 ^R6 groups; each ^R6 is independently selected from halogen, hydroxyl, CN, C1 _{- C3} alkoxy, _{C1- C3} alkyl and _{C3- C5} cycloalkyl, or the two ^R6 groups together with the carbon atom to which the two are directly attached may form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as ring members and optionally substituted with 1 to 2 groups independently selected from pendoxy and C1 _{- C3} alkyl; each R ¹³ is independently selected from H, C _{1 -} C ₄ alkyl, 4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, 4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, and C _{3 -} C ₆ cycloalkyl, wherein the C _{1 -} C ₄ alkyl, heterocycloalkyl and C _{3 -} C ₆ cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C _{1 -} C ₄ alkyl, halogen, -OH, -NR ¹⁵ R ¹⁶ , -C(=O)OR ¹⁵ , C _{1 -} C ₂ alkoxy and C _{1 -} C ₄ alkyl substituted with 1 to 2 hydroxyl groups; R ^{R 14} is selected from H, C _1- C ₄ alkyl and C _3- C ₆ cycloalkyl, wherein the C _1- C ₄ alkyl and C _3- C ₆ cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C _1- C ₄ alkyl, halogen, -OH, -NR ¹⁵ R ¹⁶ , C _1- C ₂ alkoxy and C 1 _- C ₄ alkyl substituted with 1 to 2 hydroxyl groups; or R ¹³ and R ¹⁴ together with the nitrogen atom to which both are directly attached can form a 4-6 membered ring which optionally contains additional N, O or S as a ring member and is optionally substituted with one to three groups selected from C _1- C ₂ alkyl, C _1- C ₂ alkoxy, pendoxy and hydroxyl groups; R ¹⁵ and R ^{R 16} is each independently selected from H and C _1- C ₄ alkyl, and each R ¹⁷ is independently selected from H, C _1- C ₄ alkyl and C ₃ -C ₈ cycloalkyl. Typically, for these methods, the compounds of formula (A) and formula (I-2) are combined or mixed together in the presence of an inert solvent under conditions suitable for forming an amide bond, including methods known for peptide synthesis. For example, in the case where X represents -OH, any of a wide range of dehydrating agents suitable for forming amide bonds from amines and carboxylic acids can be used. Some of these dehydrating agents are illustrated by the examples herein and include carbodiimides (e.g., dicyclohexylcarbodiimide; diisopropylcarbodiimide; EDC; and the like). Optionally, the reaction with carbodiimide can be promoted by the presence of an activator such as HOBt, HOAt, N-hydroxysuccinimide or the like. Alternatively, the acid of formula (A) or its salt can be activated by reacting with an activator such as HATU, HBTU, BOP, PyBOP, PyBrOP, TBTU, COMU or TFFH in the presence of a base such as triethylamine, DIPEA, DMAP, pyridine and the like, and then contacted with the amine compound of formula (I-2). Where X represents a leaving group, it may be a halide (eg Cl), or an acyl group, such as -OC(O)-OR*, wherein R* represents C ₁ -C ₆ alkyl, optionally substituted with up to three halide or C _1-3 alkoxy groups.

In certain embodiments, the compound of formula (A) is a compound of formula (VII): wherein ^RC is H; ^L is _-CH2- ; and W ^is cyclopropyl substituted by _-SO2R10 ^, _-SO2NR14R10 or ^-SO2NR13R14 , wherein ^t , ^R10 , ^{R13 and} _R14 are as defined for formula (A)

The compounds of formula (A) and (I-2) as described above and methods for preparing the compounds of the present invention using the same are also aspects of the present invention.

The invention further comprises any variant of the process according to the invention, wherein intermediate products obtainable at any stage thereof are used as starting materials and the remaining steps are carried out, or wherein the starting materials are formed in situ under the reaction conditions, or wherein the reaction components are used in the form of their salts or optically pure materials.

The invention also relates to those forms of the process in which compounds obtainable as intermediates at any stage of the process are used as starting materials and the remaining process steps are carried out, or in which the starting materials are formed under reaction conditions or used in the form of derivatives (e.g. in protected form or in the form of salts), or in which under process conditions compounds obtainable by the process according to the invention are produced and further processed in situ. Pharmaceutical compositions and routes of administration

Pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier are included within the scope of the present invention.

According to another aspect of this embodiment, the pharmaceutical composition according to the present invention further comprises a therapeutically effective amount of at least one other antiviral agent.

The compounds of the present invention can be administered by known methods, including oral, parenteral, inhalation and the like. In certain embodiments, the compounds of the present invention are administered orally in the form of pills, buccal tablets, sugar-coated tablets, capsules, solutions or suspensions. In other embodiments, the compounds of the present invention are administered by injection or infusion. Infusion is usually performed intravenously, usually over a period of about 15 minutes and 4 hours. In other embodiments, the compounds of the present invention are administered intranasally or by inhalation; inhalation methods are particularly suitable for treating respiratory tract infections. The compounds of the present invention exhibit oral bioavailability and can be administered orally.

The language "pharmaceutical composition" includes formulations suitable for administration to mammals (e.g., humans). When the compounds of the present invention are administered to mammals, such as humans, as a medicament, they can be provided by themselves or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (e.g., 0.5 to 90%) of at least one compound of formula (I) or any subgenus thereof as an active ingredient and a pharmaceutically acceptable carrier, or, as the case may be, two or more pharmaceutically acceptable carriers.

The phrase "pharmaceutically acceptable carrier" is art-recognized and includes pharmaceutically acceptable substances, compositions or vehicles suitable for administering the compounds of the invention to mammals. Carriers include liquid or solid fillers, diluents, excipients, solvents or encapsulating materials that are involved in carrying or transporting an individual formulation from one organ or part of the body to another organ or part of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter; butter) and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethanol; phosphate buffered solutions; and other nontoxic compatible substances used in pharmaceutical formulations. Typically, pharmaceutically acceptable carriers are sterile and/or substantially pyrogen-free.

Wetting agents, emulsifiers and lubricants (such as sodium lauryl sulfate and magnesium stearate) as well as coloring agents, release agents, coating agents, sweetening, flavoring and fragrance agents, preservatives and antioxidants may also be present in the composition.

Examples of pharmaceutically acceptable antioxidants include water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxymethoxyphenyl (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol and the like; and metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid and the like.

The formulations of the present invention include formulations suitable for oral, nasal, inhaled, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. The formulations are preferably presented as unit dosage forms and can be prepared by suitable methods. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of compound that produces a therapeutic effect. Generally speaking, out of 100%, this amount will be in the range of about 1% to about 99%, such as about 5% to about 70% or about 10% to about 30% of the active ingredient.

The method of preparing such formulations or compositions includes the step of combining the compound of the present invention with a carrier and, if appropriate, one or more accessory ingredients. In general, the formulation is prepared by uniformly and intimately combining the compound of the present invention with a liquid carrier or a finely powdered solid carrier or both and then shaping the product if necessary.

The formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, such as usually sucrose and gum arabic or tragacanth), powders, granules, or in the form of a solution or suspension in an aqueous or non-aqueous liquid, or in the form of an oil-in-water or water-in-oil liquid emulsion, or in the form of an elixir or syrup, or in the form of a tablet (using an inert base, such as gelatin and glycerol, or sucrose and gum arabic) and/or in the form of a mouthwash and the like, each containing a predetermined amount of the compound of the invention as the active ingredient. The compounds of the invention may also be administered in the form of a bolus, a slurry or a paste.

In the solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like) of the present invention, the active ingredient is mixed with one or more pharmaceutically acceptable carriers (such as sodium citrate or dicalcium phosphate) and/or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol and/or silicic acid; binders, such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and/or or gum arabic; humectants such as glycerol; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; solution delay agents such as wax; absorption enhancers such as quaternary ammonium compounds; wetting agents such as cetyl alcohol and glyceryl monostearate; adsorbents such as kaolin and bentonite; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof; and coloring agents. In the case of capsules, tablets and pills, the pharmaceutical composition may also contain a buffering agent. Similar types of solid compositions may also be used as fillers in soft-fill and hard-fill gelatin capsules using excipients such as lactose (milk sugar) and high molecular weight polyethylene glycols and their analogs.

Tablets can be made by compression or molding with one or more accessory ingredients as appropriate. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropylmethylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethylcellulose), a surfactant or a dispersant. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

Tablets and other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated pills, capsules, pills and granules, may be scored or prepared with coatings and shells, such as enteric coatings and other coatings, as appropriate. They may also be formulated using, for example, hydroxypropylmethylcellulose, other polymer matrices, liposomes and/or microspheres in proportions varying to provide the desired release characteristics, so as to provide slow or controlled release of the active ingredient therein. They may be sterilized, for example, by filtering through a bacteria-retaining filter, or by incorporating a sterilizing agent in the form of a sterile solid composition that can be dissolved in sterile water or some other sterile injectable medium prior to use. These compositions may also contain opacifiers as appropriate and may be of a composition that releases the active ingredient only or preferentially in a certain part of the gastrointestinal tract, in a delayed manner as appropriate. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient may also be in microencapsulated form, where appropriate with one or more of the above-mentioned excipients.

Liquid dosage forms of the compounds of the present invention for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage form may contain inert diluents (such as water or other solvents), solubilizers and emulsifiers commonly used in this technology, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuranol, polyethylene glycol and fatty acid esters of sorbitan and mixtures thereof.

Besides inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfuming agents and preservatives.

Suspensions, in addition to the active compounds, may contain suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions of the present invention for rectal or vaginal administration may be presented in the form of suppositories, which can be prepared by mixing one or more compounds of the present invention with one or more suitable non-irritating excipients or carriers including, for example, cocoa butter, polyethylene glycol, suppository wax or salicylate, and which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Formulations of the invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for topical or transdermal administration of the compounds of the invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers or propellants that may be required.

Ointments, pastes, creams and gels may contain, in addition to the active compounds of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, polysilicone, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

In addition to the compounds of the invention, powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays may additionally contain customary propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

Transdermal patches have the additional advantage of providing controlled delivery of the compounds of the invention to the body. Such dosage forms may be prepared by dissolving or dispersing the compound in a suitable medium. Absorption enhancers may also be used to enhance the flux of the compound across the skin. The rate of flux may be controlled by providing a rate controlling membrane or by dispersing the active compound in a polymer matrix or gel.

Also included within the scope of the present invention are ophthalmic formulations, eye ointments, powders, solutions and the like.

Pharmaceutical compositions of the present invention suitable for parenteral administration may comprise one or more compounds of the present invention and one or more pharmaceutically acceptable carriers, such as sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can be reconstituted into sterile injectable solutions or dispersions before use. Such compositions may contain antioxidants, buffers, bacteriostats, solutes that make the formulation isotonic with the blood of the intended recipient, or suspending or thickening agents.

Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, glycol ethers, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like) and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters (such as ethyl oleate). Proper fluidity can be maintained, for example, by the use of coating materials (such as lecithin), by maintaining the desired particle size in the case of dispersions, and by the use of surfactants.

Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers and dispersants. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride and the like in the composition. In addition, prolonged absorption of the injectable pharmaceutical form may be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of a poorly water-soluble crystalline or amorphous material. The rate of drug absorption then depends on its dissolution rate, which in turn can depend on the size and morphology of the crystals. Alternatively, delayed absorption of a parenterally administered drug form can be accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are prepared by forming a microencapsule matrix of the compounds of the invention in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer used, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues.

The preparation of the present invention can be administered orally, parenterally, topically or rectally. It is of course administered in a form suitable for each route of administration. For example, it is administered in the form of tablets or capsules, by injection, inhalation, eye lotion, ointment, suppository, etc., by injection, infusion or inhalation, topically by lotion or ointment, and rectally by suppository.

As used herein, the phrases "parenteral administration" and "parenteral administration" mean modes of administration other than enteral and topical administration, usually by injection, and include, but are not limited to, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcutaneous, intraarticular, subcapsular, subarachnoid, intraspinal, and intrasternal injection and infusion. In some embodiments, the compounds of the present invention are administered by intravenous infusion. Infusions can be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds of the present invention are administered by infusion at intervals between 15 minutes and 4 hours, usually between 0.5 and 3 hours. The infusion can be used once a day, twice a day, or up to three times a day.

As used herein, the phrases "systemic administration," "systemic administration," "peripheral administration," and "peripheral administration" mean administration of a compound, drug, or other material other than directly into the central nervous system so that it enters the patient's system and is thereby metabolized and other similar processes, such as subcutaneous administration.

These compounds can be administered to humans and other animals for therapy by any suitable route of administration, including oral, nasal (e.g., by spray), rectal, vaginal, parenteral, intracisternal, and topical (e.g., by powders, ointments, or drops, including buccal and sublingual).

Regardless of the route of administration selected, the compounds of the present invention and/or the pharmaceutical compositions of the present invention which can be used in a suitable hydrated form are formulated into pharmaceutically acceptable dosage forms by methods known to those skilled in the art.

Actual dosage levels of the active ingredients in the pharmaceutical compositions of the invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound of the invention being employed, or its ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or substances used in combination with the particular compound being employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and similar factors.

A physician or veterinarian of ordinary skill can determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian may initially administer a compound of the invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

In general, the suitable daily dose of the compounds of the present invention is the amount of the compound that is the minimum dose effective to produce a therapeutic effect. This effective dose will generally depend on the factors described above. In general, the intravenous and subcutaneous doses of the compounds of the present invention for patients will range from about 0.0001 to about 100 mg/kg body weight/day when used for a specified effect, more preferably, for example, about 0.01 to about 50 mg/kg/day, or about 0.1 to about 20 mg/kg/day. An effective amount is an amount for preventing or treating a viral infection such as CMV or another herpes virus.

If necessary, the effective daily dose of the active compound can be administered daily in a single dose, or as a unit dosage form divided into two, three, four, five, six or more sub-doses at appropriate intervals throughout the day. Compounds delivered orally or by inhalation are generally administered in one to four doses per day. Compounds delivered by injection are generally administered once a day or once every other day. Compounds delivered by infusion are generally administered in one to three doses per day. When multiple doses are administered in one day, the doses may be administered at intervals of about 4 hours, about 6 hours, about 8 hours or about 12 hours.

Although the compounds of the invention can be administered alone, they are generally administered as pharmaceutical compositions, such as those described herein. Thus, the methods of using the compounds of the invention include administering the compounds in a pharmaceutical composition, wherein at least one compound of the invention is admixed with a pharmaceutically acceptable carrier prior to administration.

Various embodiments of the pharmaceutical compositions of the present invention are described herein. It should be recognized that the features specified in each embodiment can be combined with other specified features to provide other embodiments. The following examples are representative of the pharmaceutical compositions of the present invention. Example 171. A pharmaceutical composition comprising a compound of formula (I) or a compound according to any one of Examples 1 to 153 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. Example 172. The pharmaceutical composition of Example 154, further comprising at least one other antiviral agent. Embodiment 173. The pharmaceutical composition of embodiment 155, wherein the at least one other antiviral agent is selected from: herpes virus entry inhibitors; herpes virus early transcription event inhibitors; herpes virus helicase-primase inhibitors; herpes virus DNA polymerase inhibitors, such as ganciclovir (Cytovene®), valganciclovir (Valcyte®; Cymeval®), cidofovir (Vistide® ), foscavir®, CMX001, cyclopropavir (MBX-400), and valaciclovir (Valtrex®; Zelitrex®); UL97 kinase inhibitors, such as Maribavir; herpes virus protease inhibitors; herpes virus terminalase inhibitors, such as AIC246 (Letermovir); herpes virus maturation inhibitors; other inhibitors, such as artesunate; CMV vaccines, such as TransVax, and herpes virus biologics, such as Cytogam (Cytotect®). Embodiment 174. A pharmaceutical composition comprising a compound of formula (I) or a compound according to any one of embodiments 154 to 170 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. Embodiment 175. The pharmaceutical composition of embodiment 174, further comprising at least one other antiviral agent. Embodiment 176. The pharmaceutical composition of embodiment 175, wherein the at least one other antiviral agent is selected from: herpes virus entry inhibitors; herpes virus early transcription event inhibitors; herpes virus helicase-initiase inhibitors; herpes virus DNA polymerase inhibitors, such as ganciclovir (Cytovene®), valganciclovir (Valcyte®; Cymeval®), cidofovir (Vistide®), foscarnet (Foscavir®), CMX001, cipropavir (MBX-400) and valacyclovir (Valtrex®; Zelitrex®); UL97 kinase inhibitors, such as maribavir; herpes virus protease inhibitors; herpes virus terminal enzyme inhibitors, such as AIC246 (Letramuvir); herpes virus maturation inhibitors; other inhibitors, such as artesunate; CMV vaccines, such as TransVax, and herpes virus biologics, such as Cytotect®. Pharmacology and efficacy

Another aspect of the present invention relates to a method for treating or preventing herpes virus diseases and/or infections in humans, which comprises administering to humans an antiviral effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, together or separately.

Another aspect of the present invention is a method for inhibiting the replication of CMV or another herpes virus, which comprises exposing the virus to an effective amount of a compound of formula (I) or a salt thereof under conditions that inhibit viral replication. This method can be implemented in vitro or in vivo.

The use of the compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing herpes virus diseases and/or infections (including CMV) in humans also falls within the scope of the present invention.

Another embodiment of the present invention provides a compound as described above or a pharmaceutically acceptable salt thereof as a drug.

The present invention also provides the use of a pharmaceutical composition as described herein for treating CMV infection or other herpes virus in a human suffering from or at risk of suffering from CMV infection or other herpes virus.

The present invention also provides the use of a pharmaceutical composition as described herein for treating CMV disease or other herpes infection in a human suffering from CMV disease or other herpes virus infection or at risk of suffering from such disease.

Another aspect of the present invention is a product comprising a composition effective for treating herpes virus diseases and/or infections; and a packaging material comprising a label indicating that the composition can be used to treat diseases and/or infections caused by herpes viruses such as CMV; wherein the composition comprises a compound of formula (I) according to the present invention or a pharmaceutically acceptable salt thereof.

The scope of the present invention further includes the use of the compound of formula (I) or a salt thereof for inhibiting CMV replication.

The compounds of the present invention can be used in a dosage range of 0.01 to 100 mg/kg body weight per day, for example 0.1 to 50 mg/kg body weight. Each dosage unit preferably contains 5% to 95% active compound (w/w). For example, such preparations contain 20% to 80% active compound.

Of course, the actual pharmaceutically effective amount or therapeutic dose will depend on factors known to those skilled in the art, such as the age and weight of the patient, the route of administration, and the severity of the disease. In any case, the combination will be administered in an amount and manner that allows the delivery of a pharmaceutically effective amount based on the patient's unique condition.

The "effective amount" of a compound is an amount required or sufficient to treat or prevent viral infection and/or a disease or condition described herein. In one example, the effective amount of a herpes virus or CMV DNA polymerase inhibitor of Formula I is an amount sufficient to treat a viral infection in an individual. In another example, the effective amount of a DNA polymerase inhibitor is an amount sufficient to treat a viral infection (such as, but not limited to, CMV, VZV, or EBV) in an individual requiring such treatment. The effective amount can vary depending on factors such as the size and weight of the individual, the type of disease, or a specific compound of the present invention. For example, the selection of a compound of the present invention can affect the elements that constitute an "effective amount". One of ordinary skill would be able to study the factors contained herein and make determinations regarding the effective amounts of the compounds of the present invention without undue experimentation.

The dosing regimen may affect what constitutes an effective amount. The compounds of the invention may be administered to a subject before or after the onset of a viral infection. In addition, several divided doses and staggered doses may be administered daily or sequentially, or the dose may be a continuous infusion, or may be a bolus injection. In addition, the dose of the compounds of the invention may be proportionally increased or decreased as indicated by the exigencies of the treatment or prevention situation.

The compounds of the invention are useful for treating conditions, disorders or diseases as described herein, or for the manufacture of pharmaceutical compositions for treating such diseases. The invention provides methods of using the compounds of the invention for treating such diseases or for the manufacture of pharmaceutical compositions having the compounds of the invention for treating such diseases.

Another aspect of the present invention relates to a method for treating a viral disease and/or infection in a human, the method comprising administering to a human an antivirally effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, together or separately, wherein the viral disease or infection is selected from CMV infection in an immunocompromised patient (e.g., a transplant recipient), congenital CMV, genital herpes, oral herpes (cold sores), herpetic keratitis, neonatal herpes, herpetic encephalitis, varicella (chickenpox), herpes zoster (shingles), infectious mononucleosis, post-transplant lymphoproliferative disease (PTLD), Castleman's disease, and hemophagocytic lymphohistiocytosis.

Another aspect of the present invention relates to a method for treating a disease that can be induced/aggravated/accelerated by herpes virus infection in a human, the method comprising administering to the human an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), chylous diarrhea, and type 1 diabetes.

Another aspect of the present invention relates to a method for treating a disease that can be induced/aggravated/accelerated by herpes virus infection in a human, the method comprising administering to the human an effective amount of a compound of the present invention, a pharmaceutically acceptable salt thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), chylous diarrhea, and type 1 diabetes.

Another aspect of the present invention is the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a disease that can be induced/aggravated/accelerated by herpes virus infection, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), chylous diarrhea and type 1 diabetes.

Another aspect of the present invention is the use of the compound of the present invention or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating or preventing a disease that can be induced/aggravated/accelerated by herpes virus infection, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), chylous diarrhea and type 1 diabetes.

Another aspect of the invention is the use of a pharmaceutical composition as described herein for treating a viral disease and/or infection in a human, wherein the viral disease or infection is selected from CMV infection, congenital CMV, genital herpes, oral herpes (cold sores), herpetic keratitis, neonatal herpes, herpetic encephalitis, varicella (chickenpox), herpes zoster (shingles), infectious mononucleosis, post-transplant lymphoproliferative disease (PTLD), Castleman's disease and hemophagocytic lymphohistiocytosis in an immunocompromised patient (e.g., a transplant recipient).

Another aspect of the present invention is the use of the pharmaceutical composition as described herein for treating a disease that can be induced/aggravated/accelerated by herpes virus infection, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), chylous diarrhea and type 1 diabetes.

Another aspect of the present invention is the use of the pharmaceutical composition as described herein for treating a disease that can be induced/aggravated/accelerated by herpes virus infection, wherein the disease is selected from Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), chylous diarrhea and type 1 diabetes.

Various embodiments of the treatment and use of the compounds of the present invention are described herein. It should be recognized that the features specified in each embodiment can be combined with other specified features to provide other embodiments. The following examples are representative of the treatment and use of the compounds of the present invention. Example 177. A method of treating herpes virus infection, comprising administering to a patient suffering from herpes virus infection a compound of formula (I) of any one of Examples 1-153 or a pharmaceutical composition comprising a compound of formula (I) or a compound of any one of Examples 1-153. Embodiment 178. The method of embodiment 177, wherein the herpes virus is selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), herpes simplex virus (including HSV-1 and HSV-2), herpes virus 6, human herpes virus 7 and Kaposi's sarcoma-associated herpes virus. Embodiment 179. A method for treating herpes virus infection, comprising administering to a patient suffering from herpes virus infection a compound of formula (I) of any one of embodiments 154-170 or a pharmaceutical composition comprising a compound of formula (I) or a compound of any one of embodiments 154-170. Embodiment 180. The method of embodiment 179, wherein the herpes virus is selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), herpes simplex virus (including HSV-1 and HSV-2), herpes virus 6, human herpes virus 7 and Kaposi's sarcoma-associated herpes virus. Embodiment 181. The use of a compound of any one of embodiments 1-170, or a pharmaceutically acceptable salt thereof, for preparing a medicament for treating a viral infection. Embodiment 182. A compound for treating a viral infection in a patient in need thereof, comprising a compound of any one of embodiments 1-170. Embodiment 183. A compound as disclosed in embodiment 1-262. Embodiment 184. Use of the compound of any one of Embodiments 1-170 and 183 for treating viral infection. Combination therapy

In some embodiments, the compound of formula (I) is co-administered with at least one other agent selected from the group consisting of a herpes virus entry inhibitor, a herpes virus early transcriptional event inhibitor, a herpes virus helicase-primase inhibitor, another herpes virus DNA polymerase inhibitor, a UL97 kinase inhibitor, a herpes virus protease inhibitor, a herpes virus terminase inhibitor, a herpes virus maturation inhibitor, an inhibitor of another target in the herpes virus life cycle, a herpes virus vaccine, and a herpes virus biologic. In some embodiments, the herpes virus is CMV.

These other agents may be combined with the compounds of the present invention to produce a single pharmaceutical dosage form. Alternatively, these other agents may be administered to the patient separately as part of a multi-dose form, such as using a kit. Such other agents may be administered to the patient before, at the same time, or after administration of the compounds of the present invention or their pharmaceutically acceptable salts.

When the compositions of the invention comprise a combination of a compound of the invention and one or more other therapeutic or prophylactic agents, both the compound and the other agent should be present at dosage levels of between about 10% to 100%, e.g., between about 10% and 80%, of the dose normally administered in a single treatment regimen.

Antiviral agents contemplated for use in such combination therapies include agents (compounds or biologics) that are effective in inhibiting virus formation and/or replication in humans, including but not limited to agents that interfere with host or viral mechanisms necessary for virus formation and/or replication in humans. Such agents may be selected from: herpes virus entry inhibitors; herpes virus early transcriptional event inhibitors; herpes virus helicase-primase inhibitors; herpes virus DNA polymerase inhibitors, such as ganciclovir (Cytovene®), valganciclovir (Valcyte®; Cymeval®), cidofovir (Vistide®), foscarnet (Foscavir®), CMX001, cipropavir (MBX-400), and valacyclovir (Valtrex®; Zelitrex®); UL97 kinase inhibitors, such as maribavir; herpes virus protease inhibitors; herpes virus terminase inhibitors, such as AIC246 (Letramuvir); herpes virus maturation inhibitors; other inhibitors, such as artesunate; CMV vaccines, such as TransVax, and herpes virus biologics, such as Cytotect®.

The compounds of the present invention may also be used in combination with other agents (combination partners), such as other antiviral agents of Formula I or other than Formula I, to treat viral infections in an individual.

The term "combination" means a fixed combination in a unit dosage form, separate dosage forms suitable for simultaneous or sequential use, or a kit of parts for combined administration, wherein the compound of the invention and the combination partner can be independently administered simultaneously or separately within a time interval that specifically allows the combination partner to exhibit a cooperative (e.g., synergistic) effect, or any combination thereof.

In certain embodiments of the invention, the compounds of the invention are used in combination with a second antiviral agent, such as those set forth herein.

The second antiviral agent can be administered in combination with the compound of the present invention, wherein the second antiviral agent is administered before, simultaneously with, or after the compound of the present invention. When it is necessary to administer the compound of the present invention and the second agent simultaneously and the administration route is the same, the compound of the present invention can be formulated together with the second agent into the same dosage form. Examples of dosage forms containing the compound of the present invention and the second agent are tablets or capsules.

In some embodiments, the combination of the compounds of the present invention and a second antiviral agent can provide synergistic activity. The compounds of the present invention and the second antiviral agent can be administered together, separately but simultaneously, or sequentially. Combination use of the compounds of the present invention and immunomodulators

The compounds and compositions described herein can be used or administered in combination with one or more therapeutic agents that act as immunomodulators (e.g., activators of co-stimulatory molecules or inhibitors of immunosuppressive molecules) or vaccines. The planned death 1 (PD-1) protein is an inhibitory member of the expanded CD28/CTLA4 family of T cell regulatory factors (Okazaki et al. (2002) Curr Opin Immunol 14: 391779-82; Bennett et al. (2003) J. Immunol. 170:711-8). PD-1 is expressed on activated B cells, T cells, and monocytes. PD-1 is an immunosuppressive protein that negatively regulates TCR signaling (Ishida, Y. et al. (1992) EMBO J. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec 29) Immunol. Immunother. 56(5):739-745) and is upregulated in chronic infection. The interaction between PD-1 and PD-L1 can act as an immune checkpoint that can lead to, for example, a decrease in infiltrating lymphocytes, a decrease in T cell receptor-mediated proliferation, and/or immune evasion of cancerous or infected cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immunosuppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2; when the interaction between PD-1 and PD-L2 is also blocked, the effect is additive (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66). Immunomodulation can be achieved by binding to immunosuppressive proteins (e.g., PD-1) or to binding proteins that regulate inhibitory proteins (e.g., PD-L1, PD-L2).

In one embodiment, the combination therapy of the invention includes an immunomodulatory agent that is an inhibitor or antagonist of an inhibitory molecule of an immune checkpoint molecule. In another embodiment, the immunomodulatory agent binds to a protein that naturally inhibits an immunosuppressive checkpoint molecule. When used in combination with an antiviral compound, these immunomodulators can enhance the antiviral response and thus enhance the efficacy relative to treatment with the antiviral compound alone.

The term "immune checkpoint" refers to a group of molecules on the cell surface of CD4 and CD8 T cells. These molecules can effectively act as "brakes" to downregulate or inhibit adaptive immune responses. Immune checkpoint molecules include (but are not limited to) planned death 1 (PD-1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), B7H1, B7H4, OX-40, CD137, CD40 and LAG3, which directly inhibit immune cells. Immunotherapeutic agents that can serve as immune checkpoint inhibitors suitable for use in the methods of the present invention include (but are not limited to) inhibitors of PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and/or TGFR β. Inhibition of inhibitory molecules can be performed by inhibition at the DNA, RNA or protein level. In some embodiments, inhibitory nucleic acids (e.g., dsRNA, siRNA or shRNA) can be used to inhibit the expression of inhibitory molecules. In other embodiments, the inhibitor of the inhibitory signal is a polypeptide that binds to the inhibitory molecule, such as a soluble ligand, or an antibody or an antigen-binding fragment thereof.

"In combination with" is not intended to mean that the therapies or therapeutic agents must be administered at the same time and/or formulated for delivery together, but such methods of delivery are within the scope described herein. Immunomodulators may be administered simultaneously with, before, or after one or more compounds of the invention and, as appropriate, one or more other therapies or therapeutic agents. The therapeutic agents in the combination may be administered in any order. In general, each agent will be administered in an amount and/or schedule determined for that agent. It should also be understood that the therapeutic agents used in this combination may be administered together in a single composition or separately in different compositions. Generally, it is contemplated that the amount of each therapeutic agent used in the combination will not exceed the amount used alone. In some embodiments, the combined amount will be lower than the individual amounts used.

In certain embodiments, the antiviral compounds described herein are administered in combination with one or more immunomodulators, which are inhibitors of PD-1, PD-L1 and/or PD-L2. Each of these inhibitors can be an antibody, an antigen-binding fragment thereof, an immunoadhesin, a fusion protein or an oligopeptide. Examples of such immunomodulators are known in the art.

In some embodiments, the immunomodulator is an anti-PD-1 antibody selected from MDX-1106, Merck 3475, or CT-011.

In some embodiments, the immunomodulatory agent is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a homeostatic region (e.g., an Fc region of an immunoglobulin sequence).

In some embodiments, the immunomodulator is a PD-1 inhibitor, such as AMP-224.

In some embodiments, the immunomodulatory agent is a PD-L1 inhibitor, such as an anti-PD-L1 antibody.

In some embodiments, the immunomodulator is an anti-PD-L1 binding antagonist selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C or MDX-1105. MDX-1105 (also known as BMS-936559) is an anti-PD-L1 antibody described in WO2007/005874. Antibody YW243.55.S70 is an anti-PD-L1 described in WO 2010/077634.

In some embodiments, the immunomodulator is nivolumab (CAS registration number: 946414-94-4). Alternative names of nivolumab include MDX-1106, MDX-1106-04, ONO-4538 or BMS-936558. Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD-1. Nivolumab (pure 5C4) and other human monoclonal antibodies that specifically bind to PD-1 are disclosed in US 8,008,449, EP2161336 and WO2006/121168.

In some embodiments, the immunomodulator is the anti-PD-1 antibody Pembrolizumab. Pembrolizumab (also known as lambrolizumab, MK-3475, MK03475, SCH-900475 or KEYTRUDA®; Merck) is a humanized IgG4 monoclonal antibody that binds to PD-1. Pembrolizumab and other humanized anti-PD-1 antibodies are disclosed in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44; US 8,354,509; WO2009/114335; and WO2013/079174.

In some embodiments, the immunomodulator is Pilizumab (CT-011; Cure Tech), which is a humanized IgG1k monoclonal antibody that binds to PD1. Pilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO2009/101611.

Other anti-PD1 antibodies suitable for use as immunomodulators in the methods disclosed herein include AMP 514 (Amplimmune) and anti-PD1 antibodies disclosed in US 8,609,089, US 2010028330 and/or US 20120114649. In some embodiments, the anti-PD-L1 antibody is MSB0010718C. MSB0010718C (also known as A09-246-2; Merck Serono) is a monoclonal antibody that binds to PD-L1.

In some embodiments, the immunomodulator is MDPL3280A (Genentech/Roche), a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies against PD-L1 are disclosed in U.S. Patent No. 7,943,743 and U.S. Publication No. 20120039906. Other anti-PD-L1 binding agents suitable for use as immunomodulators in the methods of the present invention include YW243.55.S70 (see WO2010/077634), MDX-1105 (also known as BMS-936559), and the anti-PD-L1 binding agents disclosed in WO2007/005874.

In some embodiments, the immunomodulator is AMP-224 (B7-DCIg; Amplimmune; disclosed, for example, in WO2010/027827 and WO2011/066342), which is a PD-L2 Fc-fused soluble receptor that blocks the interaction between PD1 and B7-H1.

In some embodiments, the immunomodulator is an anti-LAG-3 antibody, such as BMS-986016. BMS-986016 (also referred to as BMS986016) is a monoclonal antibody that binds to LAG-3. BMS-986016 and other humanized anti-LAG-3 antibodies are disclosed in US 2011/0150892, WO2010/019570, and WO2014/008218.

In certain embodiments, the combination therapies disclosed herein include modulators of co-stimulatory molecules or inhibitory molecules (e.g., co-inhibitory ligands or receptors).

In one embodiment, the co-stimulatory modulator (e.g., agonist) of a co-stimulatory molecule is selected from an agonist (e.g., agonist antibody or antigen-binding fragment thereof or soluble fusion) of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 or a CD83 ligand.

In another embodiment, the combination therapy disclosed herein includes an immunomodulatory agent that is a co-stimulatory molecule, such as an agonist associated with positive signaling including the co-stimulatory domains of CD28, CD27, ICOS and/or GITR.

Exemplary GITR agonists include, for example, GITR fusion proteins and anti-GITR antibodies (e.g., bivalent anti-GITR antibodies), such as GITR fusion proteins described in U.S. Patent No. 6,111,090, European Patent No. 090505B1, U.S. Patent No. 8,586,023, PCT Publication Nos. WO 2010/003118 and 2011/090754, or GITR fusion proteins described in, for example, U.S. Patent No. 7,025,962, European Patent No. 1947183B1, U.S. Patent No. 7,812,135, U.S. Patent No. 8,388,967, U.S. Patent No. 8,591,886, European Patent No. EP 1866339, PCT Publication No. WO 2011/028683, PCT Publication No. WO 2013/039954, PCT Publication No. WO 2005/007190, PCT Publication No. WO 2007/133822, PCT Publication No. WO 2005/055808, PCT Publication No. WO 99/40196, PCT Publication No. WO 2001/03720, PCT Publication No. WO 99/20758, PCT Publication No. WO 2006/083289, PCT Publication No. WO 2005/115451, U.S. Patent No. 7,618,632 and PCT Publication No. WO 2011/051726.

In one embodiment, the immunomodulator used is a soluble ligand (e.g., CTLA-4-Ig), or an antibody or antibody fragment thereof that binds to PD-L1, PD-L2, or CTLA4. For example, an anti-PD-1 antibody molecule can be administered in combination with an anti-CTLA-4 antibody (e.g., ipilimumab). Exemplary anti-CTLA4 antibodies include Tremelimumab (an IgG2 monoclonal antibody purchased from Pfizer, formerly known as ticilimumab, CP-675,206); and ipilimumab (CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).

In one embodiment, the anti-PD-1 antibody molecule is administered after treatment with a compound of the invention as described herein.

In another embodiment, an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody or an antigen-binding fragment thereof. In another embodiment, an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-TIM-3 antibody or an antigen-binding fragment thereof. In yet other embodiments, an anti-PD-1 or PD-L1 antibody molecule is administered in combination with an anti-LAG-3 antibody and an anti-TIM-3 antibody or an antigen-binding fragment thereof. The combination of antibodies described herein may be administered separately, for example, in the form of a single antibody, or, for example, in the form of a bispecific or trispecific antibody molecule. In one embodiment, a bispecific antibody comprising an anti-PD-1 or PD-L1 antibody molecule and an anti-TIM-3 or anti-LAG-3 antibody or an antigen-binding fragment thereof is administered. In certain embodiments, the combination of antibodies described herein is used to treat cancer, e.g., a cancer as described herein (e.g., a solid tumor). The efficacy of the aforementioned combinations can be tested in animal models known in the art. For example, an animal model for testing the synergistic effect of anti-PD-1 and anti-LAG-3 is described, e.g., in Woo et al. (2012) Cancer Res. 72(4):917-27.

Exemplary immunomodulators that can be used in combination therapy include, but are not limited to, for example, afutuzumab (available from Roche®); pegfilgrastim (Neulasta®); lenalidomide (CC-5013, Revlimid®); thalidomide (Thalomid®); actimid (CC4047); and interleukins, such as IL-21 or IRX-2 (a mixture of human interleukins including interleukin 1, interleukin 2, and interferon gamma, CAS 951209-71-5, available from IRX Therapeutics).

Exemplary dosages of the immunomodulators that can be used in combination with the antiviral compounds of the present invention include an anti-PD-1 antibody molecule at a dosage of about 1 to 10 mg/kg (e.g., 3 mg/kg), and an anti-CTLA-4 antibody (e.g., ipalimumab) at a dosage of about 3 mg/kg.

Examples of embodiments of methods of using the antiviral compounds of the present invention in combination with immunomodulators include those embodiments that can be used with the compounds of formula I disclosed herein or any subgenus or species thereof: i. A method of treating a viral infection in an individual comprising administering to the individual a compound of formula (I) as described herein and an immunomodulator. ii. The method of embodiment i, wherein the immunomodulator is an activator of a co-stimulatory molecule or an inhibitor of an immune checkpoint molecule. iii. The method of any one of embodiments i and ii, wherein the activator of the co-stimulatory molecule is an agonist of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a/CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3 and CD83 ligands. iv. The method of any one of embodiments i-iii above, wherein the immune checkpoint molecule inhibitor is selected from PD-1, PD-L1, PD-L2, CTLA4, TIM3, LAG3, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4 and TGFR β. v.  The method of any one of embodiments i-iii, wherein the immune checkpoint molecule inhibitor is selected from inhibitors of PD-1, PD-L1, LAG-3, TIM-3 or CTLA4 or any combination thereof. vi.  The method of any one of embodiments i-v, wherein the immune checkpoint molecule inhibitor is a soluble ligand or antibody or an antigen-binding fragment thereof that binds to an immune checkpoint molecule. vii.  The method of any one of embodiments i-vi, wherein the antibody or an antigen-binding fragment thereof is from IgG1 or IgG4 (e.g., human IgG1 or IgG4). viii. The method of any one of embodiments i-vii, wherein the antibody or antigen-binding fragment thereof is altered, such as mutated, to increase or decrease one or more of the following: Fc receptor binding, antibody glycosylation, number of cysteine residues, effector cell function, or complement function. ix. The method of any one of embodiments i-viii, wherein the antibody molecule is a bispecific or multispecific antibody molecule having a first binding specificity for PD-1 or PD-L1 and a second binding specificity for TIM-3, LAG-3, or PD-L2. x. The method of any one of embodiments i-ix, wherein the immunomodulator is an anti-PD-1 antibody selected from nivolumab, pembrolizumab, or pilizumab. xi. The method of any one of embodiments i-x, wherein the immunomodulator is an anti-PD-L1 antibody selected from YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C or MDX-1105. xii. The method of any one of embodiments i-x, wherein the immunomodulator is an anti-LAG-3 antibody molecule. xiii. The method of embodiment xii, wherein the anti-LAG-3 antibody molecule is BMS-986016. xiv. The method of any one of embodiments i-x, wherein the immunomodulator is an anti-PD-1 antibody molecule administered by injection (e.g., subcutaneously or intravenously) at a dose of about 1 to 30 mg/kg, such as about 5 to 25 mg/kg, about 10 to 20 mg/kg, about 1 to 5 mg/kg, or about 3 mg/kg, such as once a week to once every 2, 3, or 4 weeks. xv. The method of embodiment xiv, wherein the anti-PD-1 antibody molecule is administered every other week at a dose of about 10 to 20 mg/kg. xvi. The method of embodiment xv, wherein the anti-PD-1 antibody molecule, such as nivolumab, is administered intravenously at a dose of about 1 mg/kg to 3 mg/kg, such as about 1 mg/kg, 2 mg/kg, or 3 mg/kg every two weeks. xvii. The method of embodiment xv, wherein the anti-PD-1 antibody molecule (e.g., nivolumab) is administered intravenously at a dose of about 2 mg/kg at intervals of 3 weeks. Example

The present invention is further illustrated by the following examples, which should not be construed as limiting. The assays used throughout the examples are well established in the art: demonstration of efficacy in these assays is generally considered predictive of efficacy in individuals. List of abbreviations Ac Acetyl ACN or MeCN Acetonitrile AcOEt / EtOAc Ethyl acetate AcOH Acetic acid aq Aqueous solution Bn Benzyl Bu Butyl (nBu = n-butyl, tBu = tert-butyl) CDI Carbonyldiimidazole CH ₃ CN Acetonitrile DBU 1,8-Diazabicyclo[5.4.0]-undec-7-ene Boc ₂ O Di-tert-butyl dicarbonate DCE 1,2-Dichloroethane DCM Dichloromethane DIAD Diisopropyl azodicarboxylate DiBAl-H Diisobutylaluminum hydroxide DIPEA or DIEA N-Ethyldiisopropylamine DMA N,N-Dimethylacetamide DMAP Dimethylaminopyridine DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide ESI Electrospray ionization Et ₂ O Ether Et ₃ N Triethylamine Ether EtOAc Ethyl acetate EtOH Ethanol FC Flash chromatography h hours HATU Hexafluorophosphate O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyl HBTU Hexafluorophosphate O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethylurea HCl Hydrochloric acid HMPA Hexamethylphosphoramide HOBt 1-Hydroxybenzotriazole HPLC High performance liquid chromatography H ₂ O Water IPA Isopropyl alcohol L liter LC-MS Liquid chromatography-mass spectrometry LiHMDS Lithium bis(trimethylsilyl)amide MgSO ₄ Magnesium sulfate Me Methyl MeI Methyl iodide MeOH Methanol mg milligrams min minutes mL milliliters MS mass spectrometry MsCl Methanesulfonyl chloride NaHCO ₃ Sodium bicarbonate Na ₂ SO ₄ Sodium sulfate NBS N-Bromosuccinimide NCS N-Chlorosuccinimide NH ₂ OH Hydroxyamine NMO 4-Methylmorpholine N -oxide Pd/C Palladium/charcoal Pd(OH) _2Palladium hydroxide PG Protecting group Ph Phenyl Ph ₃ P Triphenylphosphine Prep Preparative type Rf Face ratio RP Reverse phase Rt Retention time RT Room temperature SFC Supercritical fluid chromatography SiO _2Silica gel SOCl _2Sulfonyl chloride T3P® Propylphosphonic anhydride TBAF Tetrabutylammonium fluoride TBDMS 3-butyldimethylsilyl TBDPS 3-butyldiphenylsilyl TBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyl tetrafluoroborate TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofuran TIPS Triisopropylsilyl TLC Thin layer chromatography TPAP Tetrapropylammonium perruthenate TsCl Toluenesulfonyl chloride TsOH Toluenesulfonic acid Preparation Key intermediates Intermediate 1 1-(Bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1)

Step 1: To a slurry of sodium cyclopropanesulfinate (5.79 g, 45.2 mmol, 1.2 equiv) in DMF (30 mL) was added benzyl 2-bromoacetate (5.97 mL, 37.7 mmol, 1.0 equiv). The resulting mixture was stirred at room temperature overnight, then diluted with _H2O and _Et2O . The layers were separated, then the aqueous layer was extracted with _Et2O . The combined organic extracts were washed with _brine , dried over _Na2SO4 , filtered, and concentrated to give benzyl 2-(cyclopropylsulfonyl)acetate (i1-a). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.34 (m, 5H), 5.26 (s, 2H), 4.09-4.03 (m, 2H), 2.76-2.67 (m, 1H), 1.31-1.24 (m, 2H), 1.09-1.02 (m, 2H).

Step 2: To a solution of benzyl 2-(cyclopropylsulfonyl)acetate (i1-a) (9.37 g, 36.8 mmol, 2.0 equiv) in DMF (350 mL) were added K ₂ CO ₃ (10.18 g, 73.7 mmol, 1.0 equiv) and 1,2-dibromoethane (3.81 mL, 44.2 mmol, 1.2 equiv). The resulting mixture was stirred at 60 °C for 12 h, then it was cooled to room temperature and diluted with Et ₂ O. The solids were removed by filtration, the filtrate was washed with water, and the aqueous layer was extracted with Et ₂ O. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered, and concentrated. The oil was purified by column chromatography (SiO ₂ , 0-100% DCM/heptane) to give benzyl 1-(cyclopropylsulfonyl)cyclopropanecarboxylate (i1-b). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.32 (m, 5H), 5.26-5.22 (m, 2H), 3.00 (tt, J = 8.09, 4.90 Hz, 1H), 1.78-1.72 (m, 2H), 1.68-1.63 (m, 2H), 1.25-1.20 (m, 2H), 1.01-0.95 (m, 2H).

Step 3: To a solution of benzyl 1-(cyclopropylsulfonyl)cyclopropanecarboxylate (i1-b) (6.53 g, 23.29 mmol) in THF (50 mL) was added _LiBH4 (2.0 M in THF, 11.65 mL, 23.29 mmol). The resulting solution was stirred at room temperature overnight, and then the reaction mixture was added to _a 2 M HCl/ice mixture. The biphasic mixture was extracted with DCM, and the combined organic extracts were dried over _Na2SO4 , filtered, and concentrated. The oil was purified by column chromatography ( _SiO2 , 0-100% EtOAc/heptane) to give (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c). TLC R _f = 0.2 (1:3 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.92 (d, J = 6.11 Hz, 2H), 2.59-2.50 (m, 2H), 1.52-1.47 (m, 2H), 1.29-1.23 (m, 2H), 1.10-1.01 (m, 4H). MS (ESI): m/z 177.1 [M+H]+.

Step 4: A solution of (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) (10.0 g, 56.7 mmol, 1.0 eq) and DPPE (16.0 g, 39.7 mmol, 0.7 eq) in THF (100 mL) was cooled to 0°C, followed by the addition of a solution of CBr4 (38.0 g, 113.5 mmol, 2.0 eq) in THF (20 mL) over 0.5 h. After 90 min at 25°C, the solids were removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography (SiO ₂ , 10-25% EtOAc/petroleum ether) to give 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1). TLC R _f = 0.5 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl3) δ 3.89 (s, 2H), 2.66 (m, 1H), 1.78-1.69 (m, 2H), 1.33-1.26 (m, 2H), 1.23-1.18 (m, 2H), 1.16-1.09 (m, 2H). Intermediate 2 1-(Bromomethyl)-1-((1-methylcyclopropyl)sulfonyl)cyclopropane (int-2)

Step 1: A solution of (1-(cyclopropylsulfonyl)cyclopropyl)methanol (30 g, 170 mmol, 1.0 eq) in DMF (300 mL) was cooled to 0 °C, then NaH (60% in mineral oil, 13.6 g, 341 mmol, 2.0 eq) was added portionwise (gas evolution). The reaction mixture was stirred at 0 °C for 0.5 h, then NaI (1.7 g, 17.0 mmol, 0.1 eq) and BnBr (29 g, 170 mmol, 1.0 eq) were added at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, then poured into saturated _NH4Cl (300 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The material was purified by trituration from EtOAc/petroleum _ether to give (((1-(cyclopropylsulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-a). ^1H NMR (400 MHz, _CDCl3 ) δ 7.38-7.32 (m, 5H), 4.59 (s, 2H), 3.82 (s, 2H), 2.70 (m, 1H), 1.51-1.49 (m, 2H), 1.22-1.20 (m, 2H), 1.03-0.98 (m, 4H).

Step 2: n -BuLi (2.5 M in hexanes, 2.16 mL, 5.40 mmol, 1.2 equiv) was added dropwise to a solution of (((1-(cyclopropylsulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-a) (1.2 g, 4.50 mmol, 1.0 equiv) in THF (20 mL) at -60 °C. The reaction was stirred at 0 °C for 30 min, then MeI (0.84 mL, 13.5 mmol, 3.0 equiv) was added at 0 °C. The reaction was stirred at 25 °C for 1 h, then it was quenched with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC to give (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b). TLC R _f = 0.4 (1:5 EtOAc/petroleum ether). MS (ESI): m/z 281.0 [M+H] ⁺ .

Step 3: A mixture of (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) (900 mg, 2.71 mmol, 1.0 equiv) and Pd/C (200 mg) in MeOH (10 mL) and AcOH (10 mL) was stirred under hydrogen atmosphere at 20 °C for 12 h. The solid was removed by filtration and the _filtrate was concentrated. The residue was diluted with water (10 mL), neutralized with saturated _Na2CO3 , and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give (1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methanol (i2-c). TLC R _f = 0.1 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 3.78 (s, 2H), 1.43 (s, 3H), 1.30-1.29 (m, 2H), 1.24-1.22 (m, 2H), 1.00-0.98 (m, 2H), 0.78-0.76 (m, 2H).

Step 4: A solution of (1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methanol) (i2-c) (220 mg, 1.16 mmol, 1.0 eq) in THF (4 mL) was cooled to -40 °C, then _Et3N (234 mg, 2.32 mmol, 2.0 eq) and MsCl (199 mg, 1.73 mmol, 1.5 eq) were added. The mixture was stirred at -40 °C for 1 h, then placed in an ice bath and LiBr (502 mg, 5.78 mmol, 5.0 eq) was added in one portion. The mixture was stirred at 25 °C for 1 h, then diluted with water (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , 10-25% EtOAc/petroleum ether) to give 1-(bromomethyl)-1-((1-methylcyclopropyl)sulfonyl)cyclopropane (int-2). TLC R _f = 0.8 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 3.95 (s, 2H), 1.70-1.65 (m, 2H), 1.58 (s, 3H), 1.51-1.46 (m, 2H), 1.33-1.27 (m, 3H), 1.01-0.95 (m, 2H). Intermediate 3 1-(bromomethyl)-1-(ethylsulfonyl)cyclopropane (int-3)

Step 1: Ethyl 1-(ethylsulfonyl)cyclopropanecarboxylate (i3-a) was obtained using the method described for the synthetic intermediate (i1-b), with the exception that benzyl 2-(cyclopropylsulfonyl)acetate (i1-a) was replaced by ethyl 2-(ethylsulfonyl)acetate. TLC R _f = 0.5 (33% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.23 (q, J = 7.2 Hz, 2H), 3.45 (q, J = 7.5 Hz, 2H), 2.02 (s, 1H), 1.78-1.72 (m, 2H), 1.66-1.60 (m, 2H), 1.38 (t, J = 7.5 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H).

Step 2: A solution of ethyl 1-(ethylsulfonyl)cyclopropanecarboxylate (i3-a) (15 g, 72.7 mmol, 1.0 eq) in THF (150 mL) was cooled to 0 °C, and _LiAlH4 (3.3 g, 87.2 mmol, 1.2 eq) was added portionwise. The mixture was allowed to warm to room temperature and stirred at that temperature for 3 hours, and then quenched with a solution of sodium hydroxide (3.3 g) in water (10 mL). The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 15-50% EtOAc/petroleum ether) to give (1-(ethylsulfonyl)cyclopropyl)methanol (i3-b). TLC R _f = 0.1 (33% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.82 (s, 2H), 3.15 (q, J = 7.6 Hz, 2H), 2.56 (s, 1H), 1.44-1.40 (m, 2H), 1.34 (t, J = 7.6 Hz, 3H), 0.97-0.93 (m, 2H).

Step 3: 1-(Bromomethyl)-1-(ethylsulfonyl)cyclopropane (int-3) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (1-(ethylsulfonyl)cyclopropyl)methanol (i3-b). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.79 (s, 2H), 3.28-3.16 (m, 2H), 1.74-1.66 (m, 2H), 1.36 (t, J = 7.5 Hz, 3H), 1.16-1.08 (m, 2H). Intermediate 4 1-(Bromomethyl)-1-(methylsulfonyl)cyclopropane (int-4)

Step 1: Methyl 1-(methylsulfonyl)cyclopropanecarboxylate (i4-a) was obtained using the method described for the synthesis of intermediate (i1-b), with the exception that benzyl 2-(cyclopropylsulfonyl)acetate (i1-a) was replaced by methyl 2-(methylsulfonyl)acetate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.81 (s, 3H), 3.20 (s, 3H), 1.84-1.79 (m, 2H), 1.70-1.65 (m, 2H).

Step 2: (1-(Methylsulfonyl)cyclopropyl)methanol (i4-b) was obtained using the method described for the synthesis of intermediate (i1-c), with the exception that 1-(cyclopropylsulfonyl)cyclopropanecarboxylic acid benzyl ester (i1-b) was replaced by 1-(methylsulfonyl)cyclopropanecarboxylic acid methyl ester (i4-a). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.92 (d, J = 5.53 Hz, 2H), 3.04 (s, 3H), 2.48 (t, J = 5.45 Hz, 1H), 1.54-1.48 (m, 2H), 1.08-1.01 (m, 2H).

Step 3: 1-(Bromomethyl)-1-(methylsulfonyl)cyclopropane (int-4) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (1-(methylsulfonyl)cyclopropyl)methanol (i4-b). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.86 (s, 1H), 3.10 (s, 3H), 1.79-1.76 (m, 2H), 1.23-1.19 (m, 2H). Intermediate 5 1-Methyl-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5)

Step 1: To a solution of 3-iodo- 1H -pyrazolo[3,4-c]pyridine (7.2 g, 29.4 mmol, 1.0 eq) in DMF (160 mL) was added NaH (60% in mineral oil, 2.4 g, 58.8 mmol, 2.0 eq) portionwise at 0°C (gas evolution). The mixture was stirred at 0°C for 30 min, followed by the addition of _CH3I (8.7 g, 61.3 mmol, 2.1 eq). After the reaction mixture was stirred at 0°C for 30 min and at 15°C for 1 h, the mixture was diluted with _H2O (300 mL) and neutralized to pH 7 with 1 M HCl. The aqueous layer was extracted with EtOAc (3 × 200 mL) and the combined organic extracts were dried over Na ₂ SO ₄ , filtered, and concentrated. The crude solid was purified by RP-HPLC to give 3-iodo-1-methyl-1H-pyrazolo[3,4-c]pyridine (i5-a). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.86 (s, 1H), 8.31 (d, J = 5.6 Hz, 1H), 7.30 (d, J = 5.6 Hz, 1H), 4.15 (s, 3H). MS (ESI): m/z 260.1 [M+H] ⁺ .

Step 2: To a solution of 3-iodo-1-methyl- 1H -pyrazolo[3,4-c]pyridine (i5-a) (4.0 g, 15.4 mmol, 1.0 eq) in EtOH (150 mL) were added Pd(dppf) _Cl2 (3.95 g, 5.41 mmol, 0.35 eq) and _Et3N (6.44 mL, 46.3 mmol, 3.0 eq). The mixture was stirred under CO atmosphere (50 psi) at 40 °C for 24 h and then concentrated. The residue was dry loaded onto silica gel and purified by column chromatography (SiO ₂ , 20-75% EtOAc/petroleum ether) to give ethyl 1-methyl- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate (i5-b). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.97 (d, J = 1.0 Hz, 1H), 8.40 (d, J = 5.6 Hz, 1H), 7.98 (dd, J = 1.2, 5.6 Hz, 1H), 4.46 (q, J = 7.2 Hz, 2H), 4.22 (s, 3H), 1.42 (t, J = 7.2 Hz, 3H). MS (ESI): m/z 206.3 [M+H] ⁺ .

Step 3: To a solution of N -oxide x (221 mg, 1.0 mmol, 1.0 equiv) in DMF (3 mL) was added TFAA (1.5 mL) dropwise at 20 °C. The reaction mixture was stirred for 18 h, then it was diluted with ice water (10 mL). _The mixture was neutralized with 10% _Na2CO3 and extracted with EtOAc (4 × 3 mL). The combined organic extracts were dried _{over Na2SO4} , filtered, and concentrated. The residue was purified by column chromatography ( _SiO2 , 50% EtOAc/petroleum ether) to give 1-methyl-7-oxo-6,7-dihydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (int-5). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.08 (d, J = 7.1 Hz, 1H), 6.95 (d, J = 7.1 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 4.41 (s, 3H), 1.45 (t, J = 7.2 Hz, 3H). MS (ESI): m/z 222.1 [M+H] ⁺ . Intermediate 6 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-6)

A mixture of ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c] _{pyridine-3-carboxylate (int-5) (80 mg, 0.37 mmol, 1.0 equiv), Cs2CO3 (} 620 mg, 1.9 mmol, 5.0 equiv) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) (177 mg, 0.74 mmol, 2.0 equiv) in DMF (2 mL) was stirred at 50 °C for 12 h, then it was diluted with water (2 mL) and extracted with EtOAc (3 x 2 mL). The combined organic extracts were washed with water (4 mL) and brine (2 × 4 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (SiO ₂ , 67% EtOAc/petroleum ether) to give ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-6). TLC R _f = 0.4 (67% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.39 (br d, J = 7.2 Hz, 1H), 6.93 (br d, J = 7.3 Hz, 1H), 4.63 (s, 2H), 4.47-4.42 (m, 2H), 4.39 (s, 3H), 1.43-1.39 (m, 3H), 1.15-1.02 (m, 8H). Intermediate 7 1-Methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-7)

1-Methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-6,7-dihydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (int-7) was obtained using the method described for the synthetic intermediate (int-6), with the exception that 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by 1-(bromomethyl)-1-(methylsulfonyl)cyclopropane (int-4). TLC R _f = 0.2 (33% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.38 (d, J = 7.4 Hz, 1H), 6.93 (d, J = 7.3 Hz, 1H), 4.57 (s, 2H), 4.44 (q, J = 7.2 Hz, 2H), 4.40 (s, 3H), 3.01 (s, 3H), 1.49-1.46 (m, 2H), 1.43 (t, J = 7.2 Hz, 3H), 1.31-1.27 (m, 2H). Intermediate 8 ( Z )-2-chloro-2-(2-cyclopropylhydrazono)acetate (int-8)

Step 1: To a solution of ethyl 2-oxoacetate (2.7 g, 13.2 mmol) in THF (20 mL) at 0 °C was added K ₂ CO ₃ (6.1 g, 44.0 mmol) and cyclopropylhydrazine dihydrochloride (2.0 g, 13.8 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by preparative TLC (SiO ₂ , 50% EtOAc/petroleum ether) to give ethyl ( E )-2-(2-cyclopropylhydrazono)acetate. TLC R _f = 0.5 (50% EtOAc/petroleum ether). MS (ESI): m / z 157.1 [M+H] ⁺ . Step 2: To a solution of ethyl ( E )-2-(2-cyclopropylhydrazono)acetate (500 mg, 3.2 mmol) in DMF (5 mL) at 50 °C was added NCS (470 mg, 3.52 mmol). The reaction was stirred at 50 °C for 30 min, then it was diluted with water and extracted with EtOAc (2 × 20 mL). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/petroleum ether) to give ( Z )-ethyl 2-chloro-2-(2-cyclopropylhydrazono)acetate (int-8). TLC R _f = 0.5 (25% EtOAc/petroleum ether). MS (ESI): m / z 191.0 [M+H] ⁺ . Intermediate 9 ( Z )-ethyl 2-bromo-2-(2-methylhydrazono)acetate (int-9)

Ethyl ( Z )-2-bromo-2-(2-methylhydrazono)acetate (int-9) was obtained using the procedure described for the synthesis of ethyl ( Z )-2-chloro-2-(2-cyclopropylhydrazono)acetate (int-8) with the exception that cyclopropylhydrazine dihydrochloride was replaced by methylhydrazine in step 1 and NCS was replaced by NBS in step 2. ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.50 (s, 1H), 4.34 (q, J = 6.9 Hz, 2H), 3.30 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H). MS (ESI): m / z 209.1 [M+H] ⁺ . Intermediate 10 1-Methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-10)

Ethyl ( Z )-2-bromo-2-(2-methylhydrazono)acetate (int-9) (9.78 g, 30.2 mmol, 1.1 eq., 93% pure) was dissolved in EtOAc (91 mL, 0.3 M), cooled to 0 °C, and 3-(N-morpholinyl)-5,6-dihydropyridin-2( 1H )-one (5.00 g, 27.4 mmol, 1.0 eq.) was added in one portion. Triethylamine (11.5 mL, 82 mmol 3.0 eq.) was added and the reaction vessel was removed from the ice bath and stirred at room temperature for 20 minutes. The reaction mixture was then heated at 77 °C for 5 hours, during which time the solution became a beige suspension. The reaction vessel was cooled in an ice bath and 5 mL of 4 N HCl was added dropwise. After stirring for 45 minutes _{, the reaction mixture was removed from the ice bath and partitioned between CH2Cl2 (50 mL) and H2O (50 mL). The organic layer was collected and the aqueous layer was extracted with CH2Cl2 ( 2 x} 50 mL) _, then the combined organic extracts were dried ( _MgSO4 ), filtered, and concentrated until solids began to fall out of solution. The solids (3.48 g) were collected by filtration and the mother liquor was concentrated and purified by column chromatography ( _SiO2 , 50-100% EtOAc/heptane) to give an additional 1.1 g of product. The solids were combined to give ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate (int-10). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.76 (br s, 1H), 4.42 (q, J = 7.1 Hz, 2H), 4.26 (s, 3H), 3.60 (dt, J = 2.7, 7.0 Hz, 2H), 3.12 (t, J = 7.0 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H). MS (ESI): m / z 288.0 [M+H] ⁺ . Intermediate 11 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11)

To a solution of ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-10) (1.0 g, 4.5 mmol, 1.0 equiv) in DMF (10 mL) was added NaH (60% in mineral oil, 360 mg, 9.0 mmol, 2.0 equiv) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) (2.2 g, 9.0 mmol, 2.0 equiv) at 25 °C (gas evolution). The resulting mixture was stirred at 25 °C for 12 h, then it was quenched with water (2 mL) and adjusted to pH 2 with 1 N HCl, then it was extracted with EtOAc (2 x 30 mL). The combined organic extracts were washed with brine (3 × 20 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11). TLC R _f = 0.2 (1:10 MeOH/DCM). MS (ESI): m / z 354.1 [M+H] ⁺ . Intermediate 12 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-12)

6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-12) was obtained using the procedure for intermediate (int-6), except that intermediate (int-5) was replaced by 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-10). MS (ESI): m/z 382.1 [M+H] ⁺ . Intermediate 13 1-Methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13)

1-Methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate (int-13) was obtained using the procedure for intermediate (int-6), except that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced by ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by 1-(bromomethyl)-1-((1-methylcyclopropyl)sulfonyl)cyclopropane (int-2). TLC R _f = 0.5 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.44 (m, 2H), 4.23 (s, 3H), 4.12 (s, 2H), 3.72-3.69 (m, 2H), 3.14-3.09 (m, 2H), 1.64-1.62 (m, 3H), 1.53-1.52 (m, 2H), 1.47-1.46 (m, 2H), 1.40 (m, 3H), 1.04 (m, 2H), 0.88-0.87 (m, 2H). MS (ESI): m/z 396.1 [M+H] ⁺ . Intermediate 14 1-Methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-14)

To a solution of ethyl 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-13) (470 mg, 1.23 mmol, 1.0 equiv) in THF (3 mL) was added a solution of NaOH (99 mg, 2.46 mmol, 2.0 equiv) in _H2O (1 mL). The reaction mixture was stirred at 25 °C for 16 h, then it was acidified to pH 3-4 with 1 N HCl, then the mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (2 × 10 mL), dried over Na ₂ SO ₄ , filtered and concentrated to give 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid (int-14). TLC R _f = 0.1 (EtOAc). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.87 (br s, 1H), 4.10 (s, 3H), 4.01 (s, 2H), 3.64 (m, 2H), 2.96 (m, 2H), 1.53 (s, 3H), 1.25-1.22 (m, 4H), 1.04 (m, 2H), 0.92 (m, 2H). MS (ESI): m/z 368.1 [M+H] ⁺ . Intermediate 15 1-(Bromomethyl)-1-((difluoromethyl)sulfonyl)cyclopropane (int-15)

Step 1: (((1-(Methylsulfonyl)cyclopropyl)methoxy)methyl)benzene (i15-a) was obtained using the procedure described for intermediate (i2-a), except that (1-(cyclopropylsulfonyl)cyclopropyl)methanol was replaced by (1-(methylsulfonyl)cyclopropyl)methanol (i4-b). TLC R _f = 0.7 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.42-7.24 (m, 5H), 4.58 (s, 2H), 3.81 (s, 2H), 3.05 (s, 3H), 1.45-1.39 (m, 2H), 1.11-1.03 (m, 2H). MS (ESI): m / z 263.1 [M+Na] ⁺ .

Step 2: ( Z )-1-((1-((Benzyloxy)methyl)cyclopropyl)sulfonyl)-3,3,3-trifluoroprop-1-en-2-ol (i15-b). A solution of LiHMDS (1.0 M in THF, 12 mL, 12.5 mmol, 1.2 equiv) in THF (30 mL) was cooled to -65 °C, and then a solution of (((1-(methylsulfonyl)cyclopropyl)methoxy)methyl)benzene (i15-a) (2.5 g, 10.4 mmol, 1.0 equiv) in THF (10 mL) was added dropwise. The mixture was stirred at -65 °C for 1 h, and then 2,2,2-trifluoroethyl 2,2,2-trifluoroacetate (3.05 g, 15.6 mmol, 1.5 equiv) was added dropwise. After 30 min at -65 °C, the reaction mixture was quenched with 1 MH ₂ SO ₄ (40 mL) and stirred at 25 °C for 16 h. The mixture was extracted with EtOAc (3 x 50 mL), and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC to give (Z)-1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-3,3,3-trifluoroprop-1-en-2-ol (i15-b). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.39-7.22 (m, 5H), 4.62 (s, 1H), 4.57-4.43 (m, 2H), 3.80 (m, 2H), 3.69 (s, 1H), 1.42-1.37 (m, 1H), 1.26-1.21 (m, 1H), 1.10-1.06 (m, 1H), 0.81-0.77 (m, 1H). MS (ESI): m / z 353.9 [M+H] ⁺ .

Step 3: 1-((1-((Benzyloxy)methyl)cyclopropyl)sulfonyl)-1,1,3,3,3-pentafluoropropane-2,2-diol (i15-c). In each of eight consistent reactions, a solution of (Z)-1-((1-((Benzyloxy)methyl)cyclopropyl)sulfonyl)-3,3,3-trifluoroprop-1-en-2-ol (i15-b) (100 mg, 0.29 mmol, 1.0 equiv) in MeCN (2 mL) was treated with Selectfluor ^® (263 mg, 0.74 mmol, 2.6 equiv). Each mixture was stirred at 40 °C for 24 h, then diluted with MeCN (3 mL) and purified by RP-HPLC. The pure substances were combined to give 1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-1,1,3,3,3-pentafluoropropane-2,2-diol (i15-c). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.41-7.21 (m, 5H), 4.55-4.45 (m, 2H), 3.88 (s, 2H), 1.56-1.45 (m, 2H), 1.36-1.27 (m, 2H).

Step 4: (((1-((difluoromethyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i15-d). A solution of 1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-1,1,3,3,3-pentafluoropropane-2,2-diol (i15-c) (300 mg, 0.768 mmol, 1.0 equiv) in THF (2 mL) and _H2O (2 mL) was treated with _Et3N (311 mg, 3.07 mmol, 4.0 equiv) and stirred at 30 °C for 0.5 h. The reaction solution was purified by RP-HPLC to give (((1-((difluoromethyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i15-d). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.44-7.27 (m, 5H), 7.18-6.86 (m, 1H), 4.55 (s, 2H), 3.72 (s, 2H), 1.44-1.38 (m, 2H), 1.32-1.27 (m, 2H). MS (ESI): m / z 294.0 [M+NH ₄ ] ⁺ .

Step 5. (1-((difluoromethyl)sulfonyl)cyclopropyl)methanol (i15-e) was obtained using the procedure described in step 2 of the synthesis of intermediate (int-2), except that (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) was replaced by (((1-((difluoromethyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i15-d). TLC R _f = 0.2 (25% EtOAc/petroleum ether).

Step 6: 1-(Bromomethyl)-1-((difluoromethyl)sulfonyl)cyclopropane (int-15) was obtained using the procedure described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (1-((difluoromethyl)sulfonyl)cyclopropyl)methanol (i15-e). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.70-6.36 (m, 1H), 3.85 (s, 2H), 1.93-1.85 (m, 2H), 1.41-1.33 (m, 2H). Intermediate 16 6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-16)

Ethyl 6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-16) was obtained using the procedure for intermediate (int-6), except that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine In the present invention, 1-(bromomethyl)-1-((difluoromethyl)sulfonyl)cyclopropane (int-15) was used to replace 1-(bromomethyl)-1-((difluoromethyl)sulfonyl)cyclopropane. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.61-6.27 (m, 1H), 4.42 (m, 2H), 4.23 (s, 3H), 4.01 (s, 2H), 3.78 (m, 2H), 3.15 (m, 2H), 1.73-1.67 (m, 2H), 1.41 (m, 3H), 1.37-1.32 (m, 2H). MS (ESI): m / z 392.0 [M+H] ⁺ . Intermediate 17 6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-17)

6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[ 3,4- ]Pyridine-3-carboxylic acid (int-17) was obtained using the procedure described for the synthesis of intermediate (int-14), with the exception that ethyl 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-13) was replaced by ethyl 6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-17). MS (ESI): m / z 364.0 [M+H] ⁺ . Intermediate 18 (Z)-2-chloro-2-(2-methylhydrazono)acetic acid ethyl ester (int-18)

Ethyl (Z)-2-chloro-2-(2-methylhydrazono)acetate (int-18) was obtained using the procedure described for the synthesis of ethyl ( Z )-2-chloro-2-(2-cyclopropylhydrazono)acetate (int-8), except that cyclopropylhydrazine dihydrochloride was replaced by methylhydrazine in step 1. ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.43 (s, 1H), 4.36 (q, J = 7.0 Hz, 2H), 3.28 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H). MS (ESI): m / z 165.1 [M+H] ⁺ . Intermediate 19 1,5-Dimethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-19)

A solution of 6-methyl-3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one (5 g, 25.48 mmol, crude, 1.0 equiv) in toluene (50 mL) was treated with _Et3N (7.73 g, 76.43 mmol, 3.0 equiv) and ethyl (Z)-2-chloro-2-(2-methylhydrazono)acetate (int-18) (5.03 g, 30.57 mmol, 1.2 equiv). The resulting mixture was stirred at 120 °C for 5 h, then it was concentrated and the residue was purified by RP-HPLC to give ethyl 1,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-19). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.43 (br s, 1H), 4.43 (q, J = 7.2 Hz, 2H), 4.25 (s, 3H), 3.98-3.88 (m, 1H), 3.26 (dd, J = 4.8, 16.8 Hz, 1H), 2.74 (dd, J = 11.2, 16.4 Hz, 1H), 1.44-1.44 (m, 1H), 1.42 (t, J = 7.2 Hz, 2H), 1.37 (d, J = 6.4 Hz, 3H). MS (ESI): m / z 238.1 [M+H] ⁺ . Intermediate 20 1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-20)

1,5-Dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-20) was obtained using the procedure described in the synthesis of (int-11), with the exception of 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c ] ethyl pyridine-3-carboxylate (int-10) was replaced with ethyl 1,5-dimethyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-19) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced with 1-(bromomethyl)-1-(methylsulfonyl)cyclopropane (int-4). MS (ESI): m / z 342.2 [M+H] ⁺ Intermediate 21 1-Cyclopropyl-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-21)

Step 1: 1-((1-(Cyclopropylsulfonyl)cyclopropyl)methyl)-3-(N-morpholinyl)-5,6-dihydropyridin-2( 1H )-one. A solution of 3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one (2.2 g, 12.1 mmol, 1.0 equiv) in DMF (22 mL) was cooled to 0 °C and NaH (60% in mineral oil, 590 mg, 14.5 mmol, 1.2 equiv) was added portionwise (gas evolution). The mixture was stirred at 25 °C for 0.5 h, then allowed to cool to 0 °C, followed by the addition of 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) (4.4 g, 18.1 mmol, 1.2 eq). After stirring at 25 °C for 12 h, the mixture was poured into water (30 mL) and extracted with EtOAc (4 x 30 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , 30-50% EtOAc/petroleum ether) to give 1-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(N-morpholinyl)-5,6-dihydropyridin-2(1 H )-one. MS (ESI): m / z 341.1 [M+H] ⁺ .

Step 2: Ethyl 1-cyclopropyl-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate (int-21) was obtained using the procedure described for the synthetic intermediate (int-19), with the exception that 6-methyl-3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one was replaced with 1-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(N-morpholinyl)-5,6-dihydropyridin-2( 1H )-one and ethyl (Z)-2-chloro-2-(2-methylhydrazono)acetate (int-18) was replaced with (Z)-2-chloro-2-(2-methylhydrazono) acetate . )-ethyl 2-chloro-2-(2-cyclopropylhydrazono)acetate (int-8). TLC R _f = 0.3 (50% EtOAc/petroleum ether). MS (ESI): m / z 408.2 [M+H] ⁺ . Intermediate 22 ( Z )-ethyl 2-bromo-2-(2-(4-methoxybenzyl)hydrazono)acetate (int-22)

Ethyl ( Z )-2-bromo-2-(2-(4-methoxybenzyl)hydrazono)acetate (int-22) was obtained using the procedure described for the synthesis of ethyl ( Z )-2-chloro-2-(2-cyclopropylhydrazono)acetate (int-8) with the exception that cyclopropylhydrazine dihydrochloride was replaced by (4-methoxybenzyl)hydrazine in step 1 and NCS was replaced by NBS in step 2. TLC _Rf = 0.4 (1:10 EtOAc/petroleum ether). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.53 (s, 1H), 7.20 (d, J = 8.4 Hz, 2H), 6.92-6.89 (m, 2H), 4.50-4.49 (m, 2H), 4.22-4.17 (m, 2H), 3.73 (s, 3H), 1.24-1.20 (m, 3H). Intermediate 23 1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-23)

Ethyl 1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-23) was obtained using the method described for intermediate (int-10), with the exception that ethyl ( Z )-2-bromo-2-(2-methylhydrazono)acetate (int-9) was replaced by ethyl (( Z )-2-bromo-2-(2-(4-methoxybenzyl)hydrazono)acetate (int-22). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40 (d, J = 8.8 Hz, 2H), 6.84-6.81 (m, 2H), 5.78 (s, 1H), 5.75 (s, 2H), 4.45-4.39 (m, 2H), 3.77 (s, 3H), 3.58-3.54 (m, 2H), 3.11-3.08 (m, 2H), 1.43-1.39 (m, 3H). MS (ESI): m / z 330.2 [M+H] ⁺ . Intermediate 24 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid (int-24)

6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid (int-24) was obtained using the method described for the synthesis of (int-11), with the exception that ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-10) was replaced with ethyl 1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-23). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 13.04-12.42 (m, 1H), 7.24 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 5.67 (s, 2H), 4.05 (s, 2H), 3.71 (s, 3H), 3.68 (s, 2H), 3.00-2.96 (m, 2H), 2.72 (s, 7H), 1.90 (s, 1H), 1.31-1.20 (m, 4H), 1.00-0.93 (m, 4H). MS (ESI): m / z 460.2 [M+H] ⁺ . Intermediate 25 4-(((2-bromoethyl)amino)methyl)benzonitrile (int-25)

A solution of 4-methylylbenzonitrile (4.8 g, 36.6 mmol, 1.0 equiv) in DCM (96 mL) was cooled to 0 °C, then 2-bromoethylamine hydrobromide (11.6 g, 56.6 mmol, 1.55 equiv) was added. The reaction mixture was stirred at 0 °C for 0.5 h, then NaBH(OAc) ₃ (23 g, 110 mmol, 3.0 equiv) and AcOH (231 mg, 3.7 mmol, 0.1 equiv) were added and the mixture was stirred at 25 °C for 12 h. The mixture was washed with water (2 x 100 mL), then _the organic layer was dried over _Na2SO4 , filtered and concentrated to give crude 4-(((2-bromoethyl)amino)methyl)benzonitrile (int-25). MS (ESI): m / z 239.2 [M+H] ⁺ . Intermediate 26 Ethyl (Z)-2-chloro-2-(2-(4-methoxybenzyl)hydrazono)acetate (int-26)

Ethyl (Z)-2-chloro-2-(2-(4-methoxybenzyl)hydrazono)acetate (int-26) was obtained using the procedure described for the synthesis of ethyl ( Z )-2-chloro-2-(2-cyclopropylhydrazono)acetate (int-8) with the exception that cyclopropylhydrazine dihydrochloride was replaced by (4-methoxybenzyl)hydrazine in step 1. TLC R _f = 0.5 (1:5 EtOAc/petroleum ether). MS (ESI): m / z 271.0 [M+H] ⁺ . Intermediate 27 Ethyl 1-(4-methoxybenzyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-27)

Step 1: 1-((1-(methylsulfonyl)cyclopropyl)methyl)-3-(N-oxolinyl)-5,6-dihydropyridin-2( 1H )-one was obtained using the method described for the synthesis of 1-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(N-oxolinyl)-5,6-dihydropyridin-2( 1H )-one in step 1 of the synthesis of intermediate (int-21), with the exception that 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced with 1-(bromomethyl)-1-((1-methylcyclopropyl)sulfonyl)cyclopropane (int-2). TLC _Rf = 0.5 (67% EtOAc/petroleum ether). MS (ESI): m / z 315.3 [M+H] ⁺ .

Step 2: 1-(4-methoxybenzyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (int-27) was obtained using the procedure described for the synthetic intermediate (int-19), with the exception that 6-methyl-3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one was replaced by 1-((1-(methylsulfonyl)cyclopropyl)methyl)-3-(N-morpholinyl)-5,6-dihydropyridin-2(1H ) -one. )-one and (Z)-2-chloro-2-(2-methylhydrazono)acetic acid ethyl ester (int-18) was replaced by (Z)-2-chloro-2-(2-(4-methoxybenzyl)hydrazono)acetic acid ethyl ester (int-26). TLC R _f = 0.5 (EtOAc). MS (ESI): m / z 462.1 [M+H] ⁺ . Intermediate 28 1-(bromomethyl)-1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane (int-28)

Step 1: A solution of sodium cyclopropanesulfinate (1.112 g, 8.68 mmol, 1.05 equiv) and tetrabutylammonium bromide (0.133 g, 0.413 mmol, 0.05 equiv) in water (4 mL) was treated with allyl bromide (1 g, 8.27 mmol, 1.0 equiv) and the resulting biphasic solution was stirred at room temperature for 24 h. The mixture was diluted with _Et2O (10 mL), the aqueous layer was removed and back extracted with _Et2O (5 mL), then the combined organic extracts were washed once with brine, dried over _MgSO4 , filtered and evaporated to give (allylsulfonyl)cyclopropane. The product was pure enough to be used without purification, but it was purified by column chromatography (SiO ₂ , 0-50% EtOAc/heptane). TLC R _f = 0.3 (2:3 EtOAc/heptane). ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.97 (ddt, J = 14.9, 10.2, 7.4 Hz, 1H), 5.51-5.43 (m, 2H), 3.76 (d, J = 7.4 Hz, 2H), 2.41 (tt, J = 8.0, 4.9 Hz, 1H), 1.24 (dt, J = 6.3, 3.2 Hz, 2H), 1.06-0.99 (m, 2H). MS (ESI): m / z 147.1 [M+H] ⁺ .

Step 2: A solution of LiHMDS (1.0 M in THF) (30.0 mL, 30.0 mmol, 2.25 equiv) was cooled to -78 °C, then a solution of (allylsulfonyl)cyclopropane (1.95 g, 13.34 mmol, 1.0 equiv) in THF (5 mL) was added dropwise over 10-15 min, followed by a THF (5 mL) wash. The resulting solution was stirred at -78 °C for 15 min, then MeI (1.835 mL, 29.3 mmol, 2.2 equiv) was added dropwise over 5 min. The resulting mixture was stirred at -78 °C for 30 min. The flask was removed from the cooling bath and the reaction was quenched with 60 mL of saturated _NH4Cl . The resulting mixture was allowed to warm to room temperature and a few mL of water was then added to dissolve the salt. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed once with brine, dried over _MgSO4 , filtered and evaporated to give the crude product. The material was purified by column chromatography ( _SiO2 , 0-50% EtOAc/heptane) to give ((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane. TLC _Rf = 0.45 (2:3 EtOAc/heptane). ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.13 (ddd, J = 15.2, 10.7, 4.1 Hz, 1H), 5.43-5.35 (m, 2H), 2.34 (dt, J = 7.7, 4.5 Hz, 1H), 1.53 (s, 6H), 1.18 (s, 2H), 0.98 (d, J = 7.7 Hz, 2H). MS (ESI): m / z 175.2 [M+H] ⁺ .

Step 3: A solution of ((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane (175 mg, 1.00 mmol, 1.0 equiv) in THF (2 mL) was cooled to -78 °C and then a solution of LDA (2.0 M in THF/heptane/ethylbenzene, 1.00 mL, 2.00 mmol, 2.0 equiv) was added dropwise along the inside of the vial over 5 min. The resulting mixture was stirred well at -78 °C for 45 min and then the cooling bath vial was removed and trioxymethylene (151 mg, 5.02 mmol, 5.0 equiv) was immediately added in one portion. The vial was capped and allowed to warm to room temperature with efficient stirring. TLC showed complete conversion of the starting material within 15 min. The reaction was quenched with 3 mL of saturated _NH4Cl to give a two-phase solution containing an insoluble white precipitate. The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 2 mL). The combined organic extracts were washed once with brine, dried over _MgSO4 , filtered and evaporated to give (1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methanol. This material was used without purification, but it could be purified by column chromatography ( _SiO2 , 0-60% EtOAc/heptane). ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.28 (dd, J = 17.5, 10.7 Hz, 1H), 5.44-5.36 (m, 2H), 3.81 (d, J = 6.2 Hz, 2H), 2.80 (t, J = 6.4 Hz, 1H), 1.55 (d, J = 7.9 Hz, 8H), 1.05-0.99 (m, 2H).

Step 4: 1-(Bromomethyl)-1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane (int-28) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.6 (1:1 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.29-6.22 (m, 1H), 5.44-5.38 (m, 2H), 3.94 (s, 2H), 1.69-1.66 (m, 2H), 1.56 (s, 6H), 1.24-1.21 (m, 2H). Intermediate 29 6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-29)

Step 1: 1-(4-methoxybenzyl)-6-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate was obtained using the method described in the synthesis of intermediate (int-6), with the exception that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced by ethyl 1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-23) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by 1-(bromomethyl)-1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane (int-28). TLC R _f = 0.5 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.30 (m, 2H), 6.82-6.80 (m, 2H), 6.26-6.16 (m, 1H), 5.71 (s, 2H), 5.46-5.39 (m, 2H), 4.46-4.37 (m, 2H), 4.05 (s, 2H), 3.76 (s, 3H), 3.68-3.64 (m, 2H), 3.08-3.05 (m, 2H), 1.56 (s, 6H), 1.54-1.52 (m, 2H), 1.41-1.37 (m, 3H), 1.01-0.98 (m, 2H).

Step 2: A solution of ethyl 1-(4-methoxybenzyl)-6-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (2.4 g, 4.65 mmol, 1.0 equiv) in DCM (10 mL) and EtOH (30 mL) was cooled to -70 °C and then a stream of ozone in oxygen was bubbled (20 min). Excess ozone was removed by bubbling oxygen for 10 min, then the solution was warmed to 0 °C and _NaBH4 (1.06 g, 27.90 mmol, 6.0 equiv) was added. The reaction mixture was stirred at 0 °C for 0.5 h, then quenched with saturated NH ₄ Cl (20 mL) and extracted with EtOAc. The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated to give ethyl 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-29). TLC R _f = 0.3 (EtOAc). MS (ESI): m / z 520.2 [M+H] ⁺ . Intermediate 30 6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-30)

6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-30) was obtained using the method described for the synthesis of intermediate (int-14) with the exception of 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid =6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced with 6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-29). MS (ESI): m / z 492.1 [M+H] ⁺ . Intermediate 31 (2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropoxy)(tert-butyl)diphenylsilane (int-31)

Step 1: Triethylamine (122 g, 1.2 mol, 1.2 eq) was added dropwise to a solution of 2-hydroxy-2-methylpropan-1-ol (106 g, 1 mol, 1.0 eq) and tert-butyl 2-bromoacetate (195 g, 1 mol, 1.0 eq) in MeOH (400 mL) at 25°C over 30 min. The reaction mixture was stirred at 25°C for 12 h, then concentrated. The residue was dissolved in EtOAc (20 mL) and the solids were removed by filtration, then the filtrate was concentrated and distilled under reduced pressure to give tert-butyl 2-((1-hydroxy-2-methylpropan-2-yl)thio)acetate. TLC R _f = 0.4 (1:5 EtOAc/petroleum ether). MS (ESI): m / z 243.2 [M+Na] ⁺ .

Step 2: Oxone ^® (280 g, 0.46 mol, 2.0 equiv) was added to a solution of tert-butyl 2-((1-hydroxy-2-methylpropan-2-yl)thio)acetate (50 g, 0.23 mol, 1.0 equiv) in acetone (0.4 L) and H ₂ O (1 L) and the mixture was stirred at 25 °C for 12 h. After the solids were removed by filtration, the filtrate was diluted with 10% Na ₂ SO ₃ (1 L) and EtOAc (1 L), and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 30 mL), and the combined organic extracts were washed with brine (2 × 50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The crude material was purified by column chromatography (SiO ₂ , 5-15% EtOAc/petroleum ether), and the solvent was concentrated to dryness, washed with petroleum ether (20 mL) and dried to give tert-butyl 2-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)acetate. TLC R _f = 0.3 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.06 (s, 2H), 3.84 (br d, J = 4.5 Hz, 2H), 3.23 (br s, 1H), 1.52 (s, 9H), 1.43 (s, 6H).

Step 3: A solution of tert-butyl 2-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)acetate (25 g, 99 mmol, 1.0 eq.), DMAP (1.2 g, 10 mmol, 0.1 eq.) and imidazole (13.5 g, 198 mmol, 2.0 eq.) in DCM (250 mL) was stirred at 25 °C for 0.5 h, followed by the addition of TBDPSCl (55 g, 198 mmol, 2.0 eq.). After stirring the reaction at 25 °C for 1.5 h, the mixture was washed with water (3 x 150 mL). The organic layer was washed with brine, dried _{over Na2SO4} , filtered and concentrated. The crude material was purified by column chromatography ( _SiO2 , 0-5% EtOAc/petroleum ether), the solvent was concentrated to dryness, washed with petroleum ether (20 mL) and dried to give tert-butyl 2-((1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)sulfonyl)acetate. TLC _Rf = 0.3 (1:10 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71-7.65 (m, 4H), 7.45-7.37 (m, 6H), 4.25 (s, 2H), 3.82 (s, 2H), 1.52 (s, 9H), 1.37 (s, 6H), 1.10 (s, 9H). MS (ESI): m / z 513.2 [M+Na] ⁺ .

Step 4: tert-Butyl 1-((1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)sulfonyl)cyclopropanecarboxylate was obtained in a similar manner to benzyl 1-(cyclopropylsulfonyl)cyclopropanecarboxylate. TLC R _f = 0.2 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70-7.62 (m, 4H), 7.42-7.38 (m, 6H), 3.91 (s, 2H), 1.73-1.66 (m, 2H), 1.52 (s, 6H), 1.49-1.44 (m, 2H), 1.39 (s, 8H), 1.10 (s, 9H).

Step 5: A solution of tert-butyl 1-((1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)sulfonyl)cyclopropanecarboxylate (3 g, 5.8 mmol, 1.0 equiv) in THF (30 mL) was cooled to 0 °C, followed by the addition of _LiAlH4 (0.44 g, 11.6 mmol, 2.0 equiv) portionwise. The reaction mixture was stirred at 0 °C for 2 h, then it was quenched by the sequential addition of water (0.5 mL) (gas evolution), 10% NaOH (1.5 mL), and water (0.5 mL). After the mixture was warmed to room temperature, the solids were removed by filtration and the filter cake was washed with EtOAc. The filtrate was concentrated and the crude material was purified by column chromatography ( _SiO2 , 0-15% EtOAc/petroleum ether), then the solvent was concentrated to dryness, washed with petroleum ether (20 mL) and dried to give (1-((1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methanol. TLC _Rf = 0.2 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.63 (m, 4H), 7.49-7.37 (m, 6H), 3.89 (s, 2H), 3.79 (d, J = 5.1 Hz, 2H), 2.77 (br t, J = 5.6 Hz, 1H), 1.54-1.49 (m, 2H), 1.48 (s, 6H), 1.10 (s, 9H), 0.97 (d, J = 1.9 Hz, 2H).

Step 6: (2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropoxy)(tert-butyl)diphenylsilane (int-31) was obtained using the method described in step 4 in the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (1-((1-((tert-butyldiphenylsilyl)oxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methanol. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.63-7.61 (m, 4H), 7.49-7.45 (m, 6H), 4.04 (s, 2H), 3.83 (s, 2H), 1.57-1.53 (m, 2H), 1.42 (s, 6H), 1.24-1.21 (m, 2H), 1.03 (s, 9H). MS (ESI): m / z 531.1 [M+Na] ⁺ . Intermediate 32 6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-32)

Step 1: 6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate was obtained using the method described for the synthesis of intermediate (int-6), with the exception that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced by ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by (2-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropoxy)(tert-butyl)diphenylsilane (int-31). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.41 (m, 2H), 4.25-4.20 (m, 3H), 4.17 (s, 2H), 3.86 (s, 2H), 3.73 (m, 2H), 3.12 (m, 2H), 1.64-1.56 (m, 2H), 1.51 (s, 6H), 1.40 (m, 3H), 1.13-1.01 (m, 2H). MS (ESI): m / z 414.2 [M+H] ⁺ .

Step 2: 6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid (int-32) was obtained using the method described for the synthesis of intermediate (int-14), with the exception that ethyl 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-13) was replaced with ethyl 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate. TLC R _f = 0.2 (1:10 MeOH/EtOAc). MS (ESI): m / z 386.1 [M+H] ⁺ . Intermediate 33 2-methyl-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)propanoic acid tert-butyl ester (int-33)

Step 1: A solution of methyl 2-hydroxyacetate (44.06 g, 415 mmol, 1.03 equiv) in MeOH (1350 mL) was treated with KOH pellets (23 g, 403 mmol, 1.0 equiv) followed by tert-butyl 2-bromo-2-methylpropanoate (90 g, 403 mmol, 1.0 equiv). The reaction was heated at 65 °C for 18 h and then cooled to room temperature before the precipitate was removed by filtration. The filter cake was washed with MeOH (540 mL) and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (1350 mL) and the organic layer was washed with water (2 x 540 mL). The combined aqueous washes were back extracted with DCM (2 x 250 mL) and the combined organic extracts were washed with brine (2 x 750 mL), dried _{over Na2SO4} and concentrated under reduced pressure. The residue was purified by column chromatography ( _SiO2 , 0-5% EtOAc/petroleum ether), then the solvent was concentrated to dryness, washed with petroleum ether (300 mL) and dried to give tert-butyl 2-((2-methoxy-2-oxoethyl)thio)-2-methylpropanoate. TLC _Rf = 0.3 (1:10 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.72 (s, 3H), 3.44 (s, 2H), 1.47 (s, 6H), 1.46 (s, 9H). MS (ESI): m / z 271.0 [M+Na] ⁺ .

Step 2: tert-butyl 2-((2-methoxy-2-oxoethyl)sulfonyl)-2-methylpropanoate was obtained using the method described in step 2 of the synthesis of intermediate (int-31), except that tert-butyl 2-((1-hydroxy-2-methylpropan-2-yl)thio)acetate was replaced with tert-butyl 2-((2-methoxy-2-oxoethyl)thio)-2-methylpropanoate. TLC R _f = 0.3 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.49 (s, 2H), 3.72 (s, 3H), 1.51 (s, 6H), 1.45 (s, 9H). MS (ESI): m / z 225.0 [M+H- ^tBu ] ⁺ .

Step 3: Methyl 1-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropanecarboxylate was obtained using the method described in step 1 of the synthesis of intermediate (int-1), with the exception that benzyl 2-(cyclopropylsulfonyl)acetate was replaced with tert-butyl 2-((2-methoxy-2-oxoethyl)sulfonyl)-2-methylpropanoate. TLC R _f = 0.5 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 3.69 (s, 3H), 1.67 (t, J = 2.8 Hz, 2H), 1.66-1.63 (m, 2H), 1.56 (s, 6H), 1.42 (s, 9H).

Step 4: Tri-tert-butoxylithium aluminum hydroxide (1.0 M in THF, 105 mL, 105 mmol, 2.0 equiv) was added to a solution of methyl 1-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropanecarboxylate (16 g, 52.2 mmol, 1.0 equiv) in THF (240 mL) at 20 °C, and the reaction mixture was heated at 50 °C for 4 h. The reaction mixture was poured into 10% _KHSO4 (500 mL) and the resulting mixture was extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (2 x 150 mL), dried _{over Na2SO4} , filtered and concentrated. The crude material was purified by column chromatography ( _SiO2 , 5-25% EtOAc/petroleum ether), then the solvent was concentrated to dryness, washed with EtOAc (20 mL) and dried to give tert-butyl 2-((1-(hydroxymethyl)cyclopropyl)sulfonyl)-2-methylpropanoate. TLC _Rf = 0.5 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 5.23 (br s, 1H), 3.81 (s, 2H), 3.40 (br s, 35H), 1.56 (s, 6H), 1.43 (s, 9H), 1.26-1.20 (m, 2H), 1.14-1.08 (m, 2H). Step 5: To a solution of tert-butyl 2-((1-(hydroxymethyl)cyclopropyl)sulfonyl)-2-methylpropanoate (1 g, 3.6 mmol, 1.0 equiv) and Et ₃ N (1.1 g, 11 mmol, 3.0 equiv) in DCM (10 mL) at 0° C. was added MsCl (0.71 g, 6.2 mmol, 1.7 equiv). After the reaction mixture was stirred at 0 °C for 1 hour, it was warmed to room temperature and stirred for 2 hours. The reaction mixture was poured into saturated _NaHCO3 (10 mL), then the organic layer was separated and washed with brine (2 x ₅ mL), dried over _Na2SO4 , filtered and concentrated to give tert-butyl 2-methyl-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)propanoate (int-33). TLC _Rf = 0.5 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.57 (s, 2H), 3.21 (s, 3H), 1.57 (s, 6H), 1.54-1.49 (m, 2H), 1.44 (s, 9H), 1.38-1.32 (m, 2H). Intermediate 34 6-((1-((1-(tert-butoxy)-2-methyl-1-oxopropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (int-34)

6-((1-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[ 3,4- ]Ethyl pyridine-3-carboxylate (int-34) was obtained using the method described for the synthesis of intermediate (int-6), with the exception that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced by ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by tert-butyl 2-methyl-2-((1-(((methylsulfonyl)oxy)methyl)cyclopropyl)sulfonyl)propanoate (int-33). MS (ESI): m / z 484.0 [M+H] ⁺ . Intermediate 35 (2-(1-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclopropyl)ethoxy)triisopropylsilane (int-35)

Step ₁ : n -BuLi (2.5 M in hexanes, 38 mL, 95 mmol, 1.2 equiv) was added dropwise to a solution of (((1-(cyclopropylsulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-a) (21.00 g, 78.84 mmol, 1.0 equiv) in THF (200 mL) at -60 °C under N2. The reaction was stirred at -60 °C for 30 min, then allyl bromide (28.61 g, 236 mmol, 3.0 equiv) was added to the mixture at -60 °C. After the addition, the resulting mixture was stirred at 25 °C for 1 h, then it was quenched with saturated _NH4Cl (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with _brine , dried over _Na2SO4 , filtered and concentrated to give (((1-((1-allylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene. TLC _Rf = 0.6 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.30 (m, 5H), 5.64-5.55 (m, 1H), 5.09-4.94 (m, 2H), 4.53 (s, 2H), 3.77 (s, 2H), 2.76 (d, J = 7.2 Hz, 2H), 1.58-1.52 (m, 2H), 1.42-1.34 (m, 2H), 1.12-1.03 (m, 2H), 0.85-0.76 (m, 2H).

Step 2: 2-(1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)ethanol was obtained using the method described in step 2 of the synthesis of intermediate (int-29), with the exception that ethyl 1-(4-methoxybenzyl)-6-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate was replaced with (((1-((1-allylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene. TLC R _f = 0.4 (50% EtOAc/petroleum ether). MS (ESI): m / z 311.3 [M+H] ⁺ .

Step 3: (2-(1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)ethoxy)triisopropylsilane was obtained using the method described in Step 5 of Example 105, except that 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile was replaced with 2-(1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)ethanol. TLC R _f = 0.8 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 8.09-8.03 (m, 1H), 7.54-7.47 (m, 1H), 7.38-7.26 (m, 3H), 4.73-4.47 (m, 2H), 3.87-3.74 (m, 3H), 2.24-2.12 (m, 2H), 1.44-1.29 (m, 4H), 1.15-0.98 (m, 23H).

Step 4: (1-((1-(2-((triisopropylsilyl)oxy)ethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol was obtained using the method described in step 3 of the synthesis of intermediate (int-2), except that (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) was replaced with (2-(1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)ethoxy)triisopropylsilane. TLC R _f = 0.6 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 3.94-3.86 (m, 4H), 2.21 (t, J = 6.8 Hz, 2H), 1.44-1.32 (m, 4H), 1.18-1.04 (m, 25H).

Step 5: (2-(1-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclopropyl)ethoxy)triisopropylsilane (int-35) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (ii-c) was replaced with (1-((1-(2-((triisopropylsilyl)oxy)ethyl)cyclopropyl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.8 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 3.98-3.87 (m, 4H), 2.23 (t, J =6.6 Hz, 2H), 1.70-1.63 (m, 2H), 1.51-1.44 (m, 2H), 1.35-1.28 (m, 2H), 1.25-1.20 (m, 2H), 1.16-1.06 (m, 21H). Intermediate 36 ((1-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropan-2-yl)oxy)(tert-butyl)dimethylsilane (int-36)

Step 1: To a solution of n-butyl cyclopropanesulfonate (5 g, 28.1 mmol, 1.0 eq) in THF (100 mL) at -78 °C was added n -BuLi (2.5 M in hexanes, 13.46 mL, 33.7 mmol, 1.2 eq) dropwise at -78 °C over 10-15 min. The resulting solution was stirred at -78 °C for 30 min, then BOMCl (7.80 mL, 33.7 mmol, 1.2 eq) was added in one portion. The resulting solution was allowed to slowly warm to room temperature and stirred at room temperature overnight, then the flask was placed in an ice bath and the reaction was quenched with brine (100 mL) and diluted with EtOAc (100 mL). After separation of the layers, the aqueous layer was extracted with EtOAc (30 mL) and the combined organic extracts were dried over MgSO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , 0-30% EtOAc/heptane) to give butyl 1-((benzyloxy)methyl)cyclopropane-1-sulfonate. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.34 (dt, J = 12.7, 7.2 Hz, 5H), 4.55 (s, 2H), 4.23 (t, J = 6.6 Hz, 2H), 3.79 (s, 2H), 1.66 (p, J = 6.9 Hz, 2H), 1.48 (d, J = 6.2 Hz, 2H), 1.37 (q, J = 7.5 Hz, 2H), 1.10 (s, 2H), 0.90 (t, J = 7.4 Hz, 3H). MS (ESI): m / z 299.2 [M+H] ⁺ .

Step 2: A mixture of butyl 1-((benzyloxy)methyl)cyclopropane-1-sulfonate (6.4 g, 21.5 mmol, 1.0 equiv) and potassium thiocyanate (2.189 g, 22.5 mmol, 1.05 equiv) in DME (100 mL) and water (100 mL) was stirred at 90 °C overnight. After the solution cooled, it was diluted with _Et2O (200 mL) and the aqueous layer was removed, followed by extraction of the organic layer with water (50 mL). The combined aqueous extracts were concentrated and dried under high vacuum to give potassium 1-((benzyloxy)methyl)cyclopropane-1-sulfonate. ¹ H NMR (500 MHz, D ₂ O) δ 7.48-7.36 (m, 5H), 4.63 (s, 2H), 3.79 (s, 2H), 1.26-1.20 (m, 2H), 0.94-0.88 (m, 2H). MS (ESI): m / z 260.1 [M+H ₂ O] ⁺ .

Step 3: To a mixture of potassium 1-((benzyloxy)methyl)cyclopropane-1-sulfonate (5.7 g, 20.26 mmol, 1.0 equiv) in DMF (5.5 mL) was added _SOCl2 (55 mL) (exothermic). The resulting mixture was stirred at 77 °C for 1 h, then concentrated. The residue was dissolved in EtOAc (250 mL) and washed with brine (2 x 50 mL), then _the organic layer was dried over _Na2SO4 , filtered and concentrated to give 1-((benzyloxy)methyl)cyclopropane-1-sulfonyl chloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.27 (m, 5H), 4.61 (s, 2H), 4.00 (s, 2H), 1.82-1.76 (m, 2H), 1.43-1.37 (m, 2H).

Step 4: To a solution of Na ₂ SO ₃ (3.48 g, 27.6 mmol, 1.0 equiv) in water (15 mL) was added NaHCO ₃ (4.64 g, 55.2 mmol, 2.0 equiv). The resulting mixture was stirred at 50 °C for 45 min, and then 1-((benzyloxy)methyl)cyclopropane-1-sulfonyl chloride (7.2 g, 27.6 mmol) was added. The resulting mixture was stirred at 50 °C overnight, then concentrated. The residue was suspended in MeOH (150 mL), the solid was removed by filtration, and the filter cake was washed with MeOH (3×50 mL). The filtrate was concentrated to obtain sodium 1-((benzyloxy)methyl)cyclopropane-1-sulfinate. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.29 (d, J = 1.9 Hz, 5H), 4.44 (s, 2H), 3.62 (s, 2H), 0.62 (d, J = 2.5 Hz, 2H), 0.22 (d, J = 2.5 Hz, 2H). MS (ESI): m / z 227.1 [M+H] ⁺ .

Step 5: A biphasic solution of sodium 1-((benzyloxy)methyl)cyclopropane-1-sulfinate (1 g, 4.03 mmol, 1.0 eq), isobutylene oxide (436 mg, 6.04 mmol, 1.5 eq) and Bu ₄ NBr (649 mg, 2.01 mmol, 0.5 eq) in CHCl ₃ (30 mL) and H ₂ O (30 mL) was stirred at 100 °C for 12 h, then the mixture was extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic extracts were washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC to give 1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropan-2-ol. TLC R _f = 0.2 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.42-7.30 (m, 5H), 4.57 (s, 2H), 3.79 (s, 2H), 3.74 (s, 1H), 3.44 (s, 2H), 1.55-1.50 (m, 2H), 1.41 (s, 6H), 1.03-0.96 (m, 2H). MS (ESI): m / z 299.3 [M+H] ⁺ .

Step 6: To a solution of 1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropan-2-ol (220 mg, 0.74 mmol, 1.0 equiv) in DCM (3 mL) was added TBSOTf (390 mg, 1.47 mmol, 2.0 equiv) and 2,6-lutidine (316 mg, 2.95 mmol, 4.0 equiv). The mixture was stirred at 25 °C for 2 h, then the reaction was diluted with water (20 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , 10-25% EtOAc/petroleum ether) to give ((1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropan-2-yl)oxy)(tert-butyl)dimethylsilane. TLC R _f = 0.8 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.30 (m, 5H), 4.55 (s, 2H), 3.77 (s, 2H), 3.43 (s, 2H), 1.52-1.46 (m, 8H), 0.99-0.92 (m, 2H), 0.85 (s, 9H), 0.08 (s, 6H).

Step 7: (1-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)sulfonyl)cyclopropyl)methanol was obtained using the method described in step 3 of the synthesis of intermediate (int-2), except that (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) was replaced with ((1-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropan-2-yl)oxy)(tert-butyl)dimethylsilane. TLC R _f = 0.5 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.89 (d, J = 6.0 Hz, 2H), 3.34 (s, 2H), 1.54 (s, 6H), 1.52-1.47 (m, 2H), 1.03-0.99 (m, 2H), 0.89-0.88 (m, 9H), 0.14 (s, 6H).

Step 8: ((1-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropan-2-yl)oxy)(tert-butyl)dimethylsilane (int-36) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (ii-c) was replaced with (1-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.8 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.89 (s, 2H), 3.44 (s, 2H), 1.79-1.73 (m, 2H), 1.55 (s, 6H), 1.21-1.15 (m, 2H), 0.88 (s, 9H), 0.14 (s, 6H). Intermediate 37 ((1 s ,3 s )-3-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane (int-37)

Step 1: To a solution of (((1-(methylsulfonyl)cyclopropyl)methoxy)methyl)benzene (7 g, 29.1 mmol, 1.0 eq) in THF (90 mL) at -60 °C under N2 atmosphere was added n - _BuLi (2.5 M in hexanes, 11.7 mL, 29.1 mmol, 1.0 eq). After 30 min at -60 °C, this solution was added dropwise to a solution of epichlorohydrin (2.6 g, 29.1 mmol, 1.0 eq) in THF (10 mL) at -60 °C, and the mixture was stirred at 20 °C for 16 h. The reaction was diluted with saturated _NH4Cl (50 mL) at 10 °C, and the mixture was extracted with EtOAc (50 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC to give (1 s ,3 s )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutan-1-ol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.28 (m, 5H), 4.59 (s, 2H), 3.80 (s, 2H), 1.92-1.86 (m, 2H), 1.74-1.68 (m, 2H), 1.29-1.24 (m, 2H), 1.20-1.14 (m, 2H). MS (ESI): m/z 297.1 [M+H] ⁺ .

Step 2: To a solution of ( 1s , 3s )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutan-1-ol (250 mg, 0.84 mmol, 1.0 equiv) in _CH2Cl2 (2 mL ₎ were added imidazole (172 mg, 2.53 mmol, 3.0 equiv) and DMAP (51 mg, 0.42 mmol, 0.5 equiv). The reaction mixture was stirred at 25 °C for 1 h, followed by the addition of TIPSCl (487 mg, 2.53 mmol, 3.0 equiv). After 15 h, the residue was concentrated and purified by RP-HPLC to give ((1 s ,3 s )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.28 (m, 5H), 4.50 (s, 2H), 4.02-3.90 (m, 2H), 3.82-3.77 (m, 2H), 1.59-1.55 (m, 2H), 1.51-1.46 (m, 6H), 1.12-0.95 (m, 23H), MS (ESI): m/z 453.1 [M+H] ⁺ .

Step 3: (1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methanol was obtained using the method described in step 3 of the synthesis of intermediate (int-2) except that (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) was replaced with ((1 s ,3 s )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutyloxy)triisopropylsilane. TLC R _f = 0.5 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.18 (s, 1H), 4.22-4.12 (m, 1H), 3.73 (s, 2H), 3.47-3.36 (m, 1H), 2.57-2.45 (m, 2H), 2.44-2.33 (m, 2H), 1.39-1.32 (m, 2H), 1.05-0.91 (m, 31H), 0.90-0.84 (m, 2H).

Step 4: ((1 s ,3 s )-3-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane (int-37) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with 1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methanol. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.31-4.23 (m, 1H), 3.82 (s, 2H), 3.69 (m, 1H), 2.71-2.61 (m, 2H), 2.53-2.42 (m, 2H), 1.77-1.70 (m, 2H), 1.17-1.11 (m, 2H), 1.08-1.00 (m, 22H). Intermediate 38 ((1 r ,3 r )-3-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane (int-38)

Step 1: To a suspension of (1s,3s)-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutan-1-ol (1.5 g, 5.06 mmol, 1.0 equiv) in THF (20 mL) was added 4-nitro-benzoic acid (845 mg, 5.06 mmol, 1.0 equiv) and _PPh3 (1.3 g, 5.06 mmol, 1.0 equiv). The reaction was cooled to 0 °C and DIAD (1.0 g, 5.06 mmol, 1.0 equiv) was added dropwise at 0 °C. The reaction was stirred at 30 °C for 16 h, followed by the addition of saturated _NaHCO3 (50 mL) at 10 °C. The mixture was extracted with EtOAc (3 x 30 mL) and the combined organic extracts were dried _{over Na2SO4} , filtered, and concentrated. Purification by RP-HPLC gave ( 1r , 3r )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutyl 4-nitrobenzoate. TLC _Rf = 0.5 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.32-8.27 (m, 2H), 8.21-8.15 (m, 2H), 7.37-7.25 (m, 5H), 5.45-5.36 (m, 1H), 4.57-4.52 (m, 2H), 4.30-4.21 (m, 1H), 3.73 (s, 2H), 3.15-3.03 (m, 2H), 2.66-2.55 (m, 2H), 1.57-1.51 (m, 2H), 1.02-0.96 (m, 2H). MS (ESI): m/z 463.1 [M+H] ⁺ .

Step 2: To a solution of ( 1r , 3r )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutyl 4-nitrobenzoate (1.0 g, 2.24 mmol, 1.0 equiv) in THF (5 mL) was added NaOH (450 mg, 11.2 mmol, 5.0 equiv) in _H2O (5 mL). The reaction was stirred at 25 °C for 16 h then concentrated. Purification by RP-HPLC gave (1r,3r)-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutan-1-ol. TLC _Rf = 0.3 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53-7.29 (m, 7H), 4.66-4.56 (m, 2H), 4.52 (s, 2H), 4.16-4.06 (m, 1H), 3.70 (s, 2H), 2.91-2.80 (m, 2H), 2.36-2.28 (m, 2H), 1.52-1.46 (m, 3H), 0.98-0.93 (m, 2H).

Step 3: ((1 r ,3 r )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane was obtained using the method described in step 2 of the synthesis of intermediate (int-37), except that (1 s ,3 s )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutan-1-ol was replaced with (1 r ,3 r )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutan-1-ol. TLC R _f = 0.8 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.28 (m, 7H), 4.59-4.53 (m, 2H), 4.52 (s, 2H), 4.12-3.99 (m, 1H), 3.71 (s, 2H), 2.84 (ddd, J = 4.5, 7.2, 14.3 Hz, 2H), 2.35-2.27 (m, 1H), 1.53-1.44 (m, 3H), 1.06-1.00 (m, 27H), 0.97-0.92 (m, 2H).

Step 4: (1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methanol was obtained using the method described in step 3 of the synthesis of intermediate (int-37) except that ((1 s ,3 s )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane was replaced with ((1 r ,3 r )-3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane. TLC R _f = 0.3 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.66-4.49 (m, 1H), 4.16-3.96 (m, 2H), 3.82 (s, 2H), 2.87 (m, 2H), 2.50-2.31 (m, 2H), 1.52-1.45 (m, 2H), 1.07-1.02 (m, 22H), 1.01-0.98 (m, 2H).

Step 5: ((1 r ,3 r )-3-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane (int-38) was obtained using the method described in step 4 of the synthesis of intermediate (int-37), except that 1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methanol was replaced with (1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.7 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.66-4.50 (m, 1H), 4.24-4.07 (m, 1H), 3.81 (s, 2H), 2.87 (m, 2H), 2.54-2.39 (m, 2H), 1.81-1.74 (m, 2H), 1.20-1.14 (m, 2H), 1.05 (d, J = 8.2 Hz, 19H). Intermediate 39 Benzyl(1-(bromomethyl)cyclopropyl)sulfane(int-39)

Step 1: To a mixture of methyl 2,4-dibromobutyrate (11.50 g, 35.39 mmol, 1.0 equiv), K ₂ CO ₃ (14.68 g, 106.18 mmol, 3.0 equiv) and n -Bu ₄ NHSO ₄ (2.40 g, 7.07 mmol, 0.2 equiv) in toluene (50 mL) was added benzylmercaptan (3.96 g, 31.86 mmol, 0.9 equiv). The mixture was stirred at 120 °C for 3 h and then concentrated. The residue was purified by column chromatography (SiO ₂ , 0-25% EtOAc/petroleum ether) to give methyl 1-(benzylthio)cyclopropanecarboxylate. TLC R _f = 0.6 (1:10 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.20 (m, 6H), 3.92 (s, 2H), 3.65 (s, 3H), 1.53 (d, J = 3.2 Hz, 2H), 1.10-1.05 (m, 2H). MS (ESI): m / z 223.1 [M+H] ⁺ .

Step 2: To a solution of methyl 1-(benzylthio)cyclopropanecarboxylate (3 g, 13.50 mmol, 1.0 equiv) in THF (30 mL) at 0 °C under _N2 was added _LiAlH4 (2.05 g, 53.98 mmol, 4.0 equiv) (gas evolution). The mixture was stirred at 25 °C for 2 h, then allowed to cool to 0 °C and the reaction was quenched by careful dropwise addition of water (2 mL) (gas evolution) and 15% NaOH (2 mL). The solids were removed by filtration, then the filter cake was washed with EtOAc (2 x 30 mL) and the filtrate was concentrated. The residue was purified by column chromatography (SiO ₂ , 0-50% EtOAc/petroleum ether) to give 1-(benzylthio)cyclopropyl)methanol. TLC R _f = 0.3 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (s, 4H), 7.26-7.22 (m, 1H), 3.83 (s, 2H), 3.38 (d, J = 6.4 Hz, 2H), 2.02-1.96 (m, 1H), 0.86 (s, 2H), 0.82-0.76 (m, 2H). MS (ESI): m / z 177.0 [M+HH ₂ O] ⁺ .

Step 3: A solution of 1-(benzylthio)cyclopropyl)methanol (2.20 g, 11.32 mmol, 1.0 equiv) in DCM (20 mL) was cooled to 0 °C and then treated with _PBr3 (3.37 g, 12.46 mmol, 1.1 equiv). The mixture was stirred at 25 °C for 2 h and then poured into ice water (100 _mL ) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over _Na2SO4 , concentrated and the residue was purified by column chromatography ( _SiO2 , 0-25% EtOAc/petroleum ether) to give benzyl(1-(bromomethyl)cyclopropyl)sulfane (int-39). TLC R _f = 0.7 (1:10 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.28 (m, 4H), 7.26-7.21 (m, 1H), 3.91 (s, 2H), 3.45 (s, 2H), 1.12-1.05 (m, 2H), 1.02-0.96 (m, 2H). Intermediate 40 3-((1-(bromomethyl)cyclopropyl)sulfonyl)-3-methyloxacyclobutane (int-40).

Step 1: A solution of sodium 1-((benzyloxy)methyl)cyclopropane-1-sulfinate (10.00 g, 40.28 mmol, 1.0 equiv) and 3-iodooxycyclobutane (9.63 g, 52.36 mmol, 1.3 equiv) in DMF (50 mL) was treated _{with Cs2CO3} (19.69 g, 60.42 mmol, 1.5 equiv) and the resulting mixture was stirred at 110 °C for 12 h. The reaction was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL), then the combined organic extracts were washed with brine (50 mL), dried _{over Na2SO4} , filtered and concentrated. The crude residue was purified by RP-HPLC to give 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxacyclobutane. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.17 (m, 5H), 4.93-4.86 (m, 2H), 4.69-4.54 (m, 3H), 4.40 (s, 2H), 3.59 (s, 2H), 1.47-1.39 (m, 2H), 0.93-0.86. MS (ESI): m / z 300.3 [M+H ₂ O] ⁺ .

Step 2: A solution of 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxacyclobutane (300 mg, 1.06 mmol, 1.0 equiv) in THF (3 mL) was cooled to -70 °C and then LiHMDS (1.6 mL, 1.6 mmol, 1.5 equiv) was added dropwise. The mixture was stirred at -70 °C for 1 hour and then MeI (0.13 mL, 2.12 mmol, 2.0 equiv) was added and the mixture was stirred at 25 °C for 1 hour. The mixture was quenched with saturated _NH4Cl (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by column chromatography ( _SiO2 , 10-25% EtOAc/petroleum ether) to give 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-3-methyloxacyclobutane. TLC _Rf = 0.6 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33-7.19 (m, 5H), 5.05 (d, J = 7.2 Hz, 2H), 4.36 (s, 2H), 4.20 (d, J = 7.2 Hz, 2H), 3.58 (s, 2H), 1.78 (s, 3H), 1.47-1.41 (m, 2H), 0.94-0.85 (m, 2H).

Step 3: (1-((3-methyloxacyclobutan-3-yl)sulfonyl)cyclopropyl)methanol was obtained using the method described in step 3 of the synthesis of intermediate (int-2), except that (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) was replaced with 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-3-methyloxacyclobutane. TLC R _f = 0.1 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.23 (d, J = 7.2 Hz, 2H), 4.46 (d, J = 7.2 Hz, 2H), 3.84 (s, 2H), 1.90 (s, 3H), 1.55-1.49 (m, 2H), 1.05-0.99 (m, 2H).

Step 4: 3-((1-(bromomethyl)cyclopropyl)sulfonyl)-3-methyloxacyclobutane (int-40) was obtained using the procedure described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (1-((3-methyloxacyclobutan-3-yl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.8 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.27 (d, J = 7.0 Hz, 2H), 4.55 (d, J = 7.3 Hz, 2H), 3.81 (s, 2H), 1.95 (s, 3H), 1.84-1.78 (m, 2H), 1.24-1.18 (m, 2H). Intermediate 41 ((3-((1-(bromomethyl)cyclopropyl)sulfonyl)oxycyclobutane-3-yl)methoxy)triisopropylsilane (int-41)

Step 1: To a solution of 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxadiazine (5.00 g, 17.7 mmol, 1.0 equiv) in THF (50 mL) was added LiHMDS (1.0 M in THF, 53.1 mL, 53.1 mmol, 3.0 equiv) dropwise at -70 °C. The mixture was stirred at -70 °C for 1 hour, then methyl chloroformate (3.35 g, 35.42 mmol, 2.0 equiv) was added, then the mixture was stirred at 25 °C for 1 hour. The reaction was quenched with water (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried _{over Na2SO4} , filtered and concentrated. The crude residue was purified by RP-HPLC to give 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxadiazine-3-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.29 (m, 5H), 5.18 (d, J = 8.0 Hz, 2H), 4.86 (d, J = 8.0 Hz, 2H), 4.47 (s, 2H), 3.83 (s, 3H), 3.65 (s, 2H), 1.57-1.52 (m, 2H), 1.05-0.99 (m, 2H). MS (ESI): m / z 358.3 [M+H ₂ O] ⁺ .

Step 2: A solution of 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxacyclobutane-3-carboxylate (3.50 g, 10.28 mmol, 1.0 equiv) in THF (40 mL) was cooled to 0 °C, then _LiAlH4 (737 mg, 20.56 mmol, 2.0 equiv) was added portionwise. The mixture was stirred at 25 °C for 1 hour, then it was quenched by the sequential addition of water (1 mL) (gas evolution), 2 N NaOH (2 mL), and water (1 mL). The mixture _was dried over _Na2SO4 , filtered, and concentrated. The residue was purified by column chromatography (SiO ₂ , 10-25% EtOAc/petroleum ether) to give (3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxacyclobutan-3-yl)methanol. TLC R _f = 0.4 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.25 (m, 6H), 5.05 (d, J = 7.6 Hz, 2H), 4.48-4.40 (m, 4H), 4.29 (d, J = 6.0 Hz, 2H), 3.69 (s, 2H), 2.80 (t, J = 6.0 Hz, 1H), 1.65-1.59 (m, 2H), 1.07-1.00 (m, 2H).

Step 3: To a stirred solution of (3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxacyclobutan-3-yl)methanol (1.00 g, 3.20 mmol, 1.0 equiv) in DMF (10 mL) at 25 °C were added imidazole (1.09 g, 16.01 mmol, 5.0 equiv) and TIPSCl (1.23 g, 6.40 mmol, 2.0 equiv), then the mixture was stirred at 80 °C for 12 h. The mixture was quenched with water (30 mL) and then extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by RP-HPLC to give ((3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxycyclobutan-3-yl)methoxy)triisopropylsilane. TLC R _f = 0.5 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.39-7.26 (m, 5H), 5.01 (d, J = 7.2 Hz, 2H), 4.82 (d, J = 6.8 Hz, 2H), 4.43 (s, 2H), 4.13 (s, 2H), 3.62 (s, 2H), 1.50-1.44 (m, 2H), 1.16-1.04 (m, 18H), 0.95-0.89 (m, 2H). MS (ESI): m / z 486.4 [M+H ₂ O] ⁺ .

Step 4: (1-((3-(((triisopropylsilyl)oxy)methyl)oxacyclobutan-3-yl)sulfonyl)cyclopropyl)methanol was obtained using the method described in step 3 of the synthesis of intermediate (int-2), except that (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) was replaced with ((3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxacyclobutan-3-yl)methoxy)triisopropylsilane. TLC R _f = 0.1 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.13 (d, J = 7.2 Hz, 2H), 4.76 (d, J = 7.2 Hz, 2H), 4.28 (s, 2H), 3.83 (d, J = 4.4 Hz,2H), 2.59 (t, J = 4.8 Hz, 1H), 1.56-1.50 (m, 2H), 1.23-1.05 (m, 25H), 1.04-0.99 (m, 2H).

Step 5: ((3-((1-(bromomethyl)cyclopropyl)sulfonyl)oxycyclobutan-3-yl)methoxy)triisopropylsilane (int-41) was obtained using the method described in step 4 of the synthesis of intermediate (int-2) with the exception of (1-((3-(((triisopropylsilyl)oxy)methyl)oxycyclobutan-3-yl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.8 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.13 (d, J = 7.2 Hz, 2H), 4.95 (d, J = 7.2 Hz, 2H), 4.22 (s, 2H), 3.83 (s, 2H), 3.69 (s, 1H), 1.78-1.73 (m, 2H), 1.23-1.10 (m, 26H). Intermediate 42 5-((1-(Bromomethyl)cyclopropyl)sulfonyl)-2,2,5-trimethyl-1,3-dioxane (int-42)

Step 1: (3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxacyclobutan-3-yl)methanol. To a stirred solution of 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)oxacyclobutane-3-carboxylate (16.00 g, 47.0 mmol, 1.0 equiv) in THF (160 mL) was added _LiAlH4 (8.92 g, 235.0 mmol, 5.0 equiv) at 25 °C. After the mixture was stirred at 25 °C for 12 h, it was quenched with water (100 mL) (gas evolution) and adjusted to pH 1-2 with 1 N HCl. The mixture was extracted with EtOAc (3 × 100 mL), and the combined organic extracts were washed with brine (100 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , 15-50% EtOAc/petroleum ether) to give 2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropane-1,3-diol. TLC R _f = 0.3 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.41-7.26 (m, 5H), 4.55 (s, 2H), 4.04-3.97 (m, 2H), 3.93-3.85 (m, 4H), 1.60-1.52 (m, 2H), 1.44-1.38 (m, 3H), 1.17-1.09 (m, 2H).

Step 2: To a stirred solution of 2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropane-1,3-diol (14.00 g, 44.5 mmol, 1.0 equiv) in THF (140 mL) was added 2,2-dimethoxypropane (46.38 g, 445.3 mmol, 10.0 equiv) and p - _TsOH.H2O (1.69 g, 8.9 mmol, 0.2 equiv) at 25°C. The mixture was stirred at 25°C for 6 h, then it was diluted with water (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organic extracts were washed with brine (100 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by column chromatography ( _SiO2 , 10-35% EtOAc/petroleum ether) to give 5-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2,2,5-trimethyl-1,3-dioxane. TLC _Rf = 0.8 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.45-7.24 (m, 4H), 4.54 (s, 2H), 4.44-4.38 (m, 1H), 4.41 (d, J = 12.2 Hz, 1H), 3.83 (s, 2H), 3.79 (d, J = 12.2 Hz, 2H), 1.56 (s, 3H), 1.54-1.49 (m, 2H), 1.38 (d, J = 12.6 Hz, 6H), 1.20-1.14 (m, 2H).

Step 3: (1-((2,2,5-trimethyl-1,3-dioxane-5-yl)sulfonyl)cyclopropyl)methanol was obtained using the method described in step 3 of the synthesis of intermediate (int-2), except that (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) was replaced with 5-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2,2,5-trimethyl-1,3-dioxane. TLC R _f = 0.2 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 4.46 (d, J = 12.2 Hz, 2H), 3.93 (s, 2H), 3.87 (d, J = 12.6 Hz, 2H), 1.58 (s, 3H), 1.49-1.45 (m, 5H), 1.40 (s, 3H), 1.17-1.11 (m, 2H).

Step 4: 5-((1-(bromomethyl)cyclopropyl)sulfonyl)-2,2,5-trimethyl-1,3-dioxane (int-42) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (1-((2,2,5-trimethyl-1,3-dioxane-5-yl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.8 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 4.33 (d, J = 13.6 Hz, 2H), 4.23 (s, 2H), 3.97 (d, J = 13.6 Hz, 2H), 1.75-1.70 (m, 2H), 1.48 (s, 3H), 1.44 (s, 3H), 1.39 (s, 3H), 1.38-1.34 (m, 2H). Intermediate 43 4-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyl-1,3-dioxacyclopentane (int-43)

Step 1: To a solution of sodium 1-((benzyloxy)methyl)cyclopropane-1-sulfinate (19 g, 76.5 mmol, 1.0 eq) in DMF (100 mL) was added allyl bromide (14 g, 115 mmol, 1.5 eq) dropwise. The reaction mixture was stirred at 25 °C for 12 h, then it was diluted with water (150 mL) and extracted with TMBE (3 x 50 mL). The combined organic extracts were washed with water (100 mL) and brine, then dried _{over Na2SO4} , filtered and concentrated. The crude material was purified by column chromatography ( _SiO2 , 5-10% EtOAc/petroleum ether) and the solvent was concentrated to dryness, washed with petroleum ether (20 mL) and dried to give (((1-(allylsulfonyl)cyclopropyl)methoxy)methyl)benzene. TLC _Rf = 0.3 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.44-7.29 (m, 5H), 5.99-5.84 (m, 1H), 5.46-5.35 (m, 2H), 4.57 (s, 2H), 3.97 (d, J = 7.5 Hz, 2H), 3.77 (s, 2H), 1.54-1.45 (m, 2H), 1.01-0.89 (m, 2H).

Step 2: (((1-((2-Methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methoxy)methyl)benzene was obtained using the method described in step 2 of the synthesis of intermediate (int-26), except that (allylsulfonyl)cyclopropane was replaced by (((1-(allylsulfonyl)cyclopropyl)methoxy)methyl)benzene. TLC _Rf = 0.4 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.43-7.28 (m, 5H), 6.20 (dd, J = 10.7, 17.5 Hz, 1H), 5.37-5.23 (m, 2H), 4.47 (s, 2H), 3.79 (s, 2H), 1.55 (s, 8H), 1.17-1.02 (m, 2H).

Step 3: A solution of (((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (11 g, 37.4 mmol, 1.0 equiv) in acetone (570 mL) and _H2O (63 mL) was treated with NMO (13.2 g, 112 mmol, 3.0 equiv) and OsO4 ( ₁ % in t -BuOH, 24 mL, 1.9 mmol, 0.05 equiv). After 12 h at 25 °C, the reaction was quenched with saturated _{aqueous Na2SO3} , the solids were removed by filtration and the filtrate was extracted with EtOAc (3 x 250 mL). The combined organic extracts were washed with water (200 mL) and brine, dried over _Na2SO4 , filtered and concentrated. The crude material was purified by column chromatography ( _SiO2 , 0-10% _EtOAc /petroleum ether), then the solvent was concentrated to dryness, washed with petroleum ether (20 mL) and dried to give 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-3-methylbutane-1,2-diol. TLC _Rf = 0.6 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.28 (m, 5H), 4.56-4.46 (m, 2H), 4.27 (td, J = 3.4, 7.2 Hz, 1H), 3.98-3.81 (m, 2H), 3.75-3.57 (m, 3H), 2.31 (br s, 1H), 1.70-1.55 (m, 2H), 1.52 (s, 3H), 1.45 (s, 3H), 1.18-1.02 (m, 2H).

Step 4: 4-(2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyl-1,3-dioxolane was obtained using the method described in step 2 of the synthesis of intermediate (int-42), except that 2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropane-1,3-diol was replaced with 3-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-3-methylbutane-1,2-diol. TLC R _f = 0.5 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.40-7.28 (m, 5H), 4.60 (t, J = 6.8 Hz, 1H), 4.51 (s, 2H), 4.02 (dd, J = 6.5, 8.9 Hz, 1H), 3.95-3.84 (m, 2H), 3.82-3.73 (m, 1H), 1.65-1.56 (m, 2H), 1.54 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 1.34 (s, 3H), 1.15-1.05 (m, 2H).

Step 5: (1-((2-(2,2-dimethyl-1,3-dioxolacyclopentan-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methanol was obtained using the method described in step 3 of the synthesis of intermediate (int-2), except that (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) was replaced with 4-(2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyl-1,3-dioxolacyclopentane. TLC R _f = 0.2 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.56 (dd, J = 6.5, 7.8 Hz, 1H), 4.08 (dd, J = 6.5, 8.6 Hz, 1H), 3.91 (dd, J = 6.0, 14.8 Hz, 2H), 3.79 (dd, J = 7.9, 8.5 Hz, 1H), 3.24-3.18 (m, 1H), 1.65-1.59 (m, 2H), 1.55 (s, 3H), 1.45 (s, 3H), 1.41 (s, 3H), 1.36 (s, 3H), 1.12-1.05 (m, 2H).

Step 6: 4-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyl-1,3-dioxolacyclopentane (int-43) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (1-((2-(2,2-dimethyl-1,3-dioxolacyclopentane-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.6 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.54 (t, J = 7.0 Hz, 1H), 4.12-4.02 (m, 3H), 3.80 (t, J = 8.1 Hz, 1H), 1.79-1.68 (m, 2H), 1.54 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H), 1.38 (s, 3H), 1.27 (br d, J = 15.3 Hz, 2H). Intermediate 44 4-(1-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclopropyl)-2,2-dimethyl-1,3-dioxacyclopentane (int-44)

Step 1: A mixture of dimethyl 2,2'-sulfonyldiacetate (13 g, 61.84 mmol, 1.0 equiv), 1,2-dibromoethane (34.85 g, 185 mmol, 3.0 equiv) and _K2CO3 (34.19 g, 247 mmol, 4.0 equiv) in _DMF (100 mL) was stirred at 60 °C for 16 h, then the solid was removed by filtration. The filtrate was concentrated and purified by column chromatography ( _SiO2 , 10-15% EtOAc/petroleum ether), then the solvent was concentrated to dryness, washed with petroleum ether (500 mL) and dried to give dimethyl 1,1'-sulfonyldicyclopropanecarboxylate. TLC R _f = 0.7 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.82-3.72 (m, 6H), 2.09-2.00 (m, 4H), 1.85-1.77 (m, 4H).

Step 2: To a solution of dimethyl 1,1'-sulfonyldicyclopropanecarboxylate (5.0 g, 19.06 mmol, 1.0 equiv) in THF (100 mL) was added _LiAlH4 (2.89 g, 76.25 mmol, 4.0 equiv). The mixture was stirred at 25 °C for 1 hour, then allowed to cool to 0 °C and the reaction was quenched by careful dropwise addition of water (3 mL) (gas evolution) and 15% NaOH (3 mL). The solids were removed by filtration and the filtrate was concentrated to give (sulfonylbis(cyclopropane-1,1-diyl))dimethanol. TLC _Rf = 0.2 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.88-3.81 (m, 4H), 1.56-1.47 (m, 4H), 1.07-0.97 (m, 4H).

Step 3: To a stirred solution of (sulfonylbis(cyclopropane-1,1-diyl))dimethanol (3 g, 14.54 mmol, 1.0 equiv) and NaH (60% in mineral oil, 581 mg, 14.54 mmol, 1.0 equiv) in THF (50 mL) at 0 °C was added TBDPSCl (4 g, 14.54 mmol, 1.0 equiv). The mixture was stirred at 25 °C for 1 h, then the solids were removed by filtration. The filtrate was purified by RP-HPLC to give (1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.4 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (dd, J = 1.4, 7.9 Hz, 4H), 7.55-7.35 (m, 6H), 3.99 (s, 2H), 3.85 (d, J = 6.0 Hz, 2H), 2.93 (t, J = 6.0 Hz, 1H), 1.53-1.46 (m, 4H), 1.09 (s, 9H), 1.04-0.97 (m, 4H).

Step 4: A mixture of (1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methanol (3.5 g, 7.87 mmol, 1.0 equiv) and IBX (6.6 g, 23.61 mmol, 3.0 equiv) in EtOAc (100 mL) was stirred at 50 °C for 16 h, then the solid was removed by filtration. The filtrate was concentrated to give 1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropanecarbaldehyde. TLC _Rf = 0.6 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.96 (s, 1H), 7.59-7.46 (m, 5H), 7.45-7.28 (m, 7H), 3.94-3.84 (m, 2H), 1.82-1.74 (m, 3H), 1.63-1.56 (m, 3H), 1.46-1.38 (m, 3H), 0.97 (s, 9H), 0.84-0.77 (m, 2H).

Step 5: A mixture of methyltriphenylphosphonium bromide (5.04 g, 14.12 mmol, 2.4 equiv) in anhydrous THF (50 mL) was cooled to 0 °C, then t -BuOK (2.22 g, 19.8 mmol, 3.4 equiv) was added portionwise over 10 min. The mixture was stirred at room temperature for 1 h, then allowed to cool to 0 °C, then a solution of 1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropanecarbaldehyde (2.5 g, 5.85 mmol, 1.0 equiv) in THF (50 mL) was added dropwise over 5 min. After 1 h, the reaction was quenched with saturated _NH4Cl (100 mL), then the layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried _{over Na2SO4} , filtered, and concentrated. The crude product was purified by RP-HPLC to give tert-butyldiphenyl((1-((1-vinylcyclopropyl)sulfonyl)cyclopropyl)methoxy)silane. TLC _Rf = 0.5 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67-7.61 (m, 4H), 7.50-7.38 (m, 6H), 6.27 (m, 1H), 5.20 (d, J = 10.4 Hz, 1H), 5.08 (d, J = 17.0 Hz, 1H), 4.07 (s, 2H), 1.54-1.46 (m, 2H), 1.43-1.34 (m, 2H), 1.15-1.10 (m, 2H), 1.09-1.03 (m, 10H), 1.02-0.94 (m, 2H).

Step 6: To a biphasic solution of tert-butyldiphenyl((1-((1-vinylcyclopropyl)sulfonyl)cyclopropyl)methoxy)silane (2 g, 4.54 mmol, 1.0 eq) in DCM (10 mL) and water (3 mL) was added NMO (0.9 g, 7.72 mmol, 1.7 eq) and _K2OsO4 · _2H2O (133 mg, 0.45 mmol, 0.1 eq). The mixture was stirred vigorously at 25 ° _C for 1 h. The mixture was concentrated and purified by RP-HPLC to give 1-(1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)ethane-1,2-diol. TLC R _f = 0.3 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.72-7.60 (m, 4H), 7.55-7.38 (m, 6H), 4.16-4.10 (m, 1H), 4.08-3.93 (m, 2H), 3.72-3.63 (m, 1H), 3.56 (dd, J = 6.4, 11.5 Hz, 1H), 1.62-1.39 (m, 4H), 1.23-1.15 (m, 1H), 1.10-1.01 (m, 3H).

Step 7: tert-Butyl((1-((1-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)diphenylsilane was obtained using the method described in step 2 of the synthesis of intermediate (int-42), with the exception that 2-((1-((benzyloxy)methyl)cyclopropyl)sulfonyl)-2-methylpropane-1,3-diol was replaced with 1-(1-((1-(((tert-butyldiphenylsilyl)oxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)ethane-1,2-diol. TLC R _f = 0.5 (1:10 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.73-7.59 (m, 4H), 7.55-7.36 (m, 6H), 4.83 (t, J = 6.5 Hz, 1H), 4.26-4.10 (m, 2H), 3.90-3.75 (m, 2H), 1.48-1.38 (m, 2H), 1.36 (s, 3H), 1.34 (s, 3H), 1.33-1.22 (m, 2H), 1.02-0.88 (m, 2H).

Step 8: (1-((1-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methanol was obtained using the method described in Step 5 of Example 105, except that 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methanol was used. =3-(((1-(2,2-dimethyl-1,3-dioxolanecyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methoxy)diphenylsilane). TLC R _f = 0.3 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.87-4.74 (m, 1H), 4.10-4.05 (m, 1H), 3.89 (m, 2H), 3.58 (m, 1H), 3.01 (m, 1H), 1.62-1.55 (m, 2H), 1.53-1.46 (m, 2H), 1.40 (s, 3H), 1.39-1.37 (m, 3H), 1.37-1.32 (m, 1H), 1.18 (m, 1H), 1.09-0.92 (m, 2H).

Step 9: 4-(1-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclopropyl)-2,2-dimethyl-1,3-dioxolacyclopentane (int-44) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (1-((1-(2,2-dimethyl-1,3-dioxolacyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methanol. TLC R _f = 0.5 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.89-4.76 (m, 1H), 4.17 (dd, J = 6.2, 8.8 Hz, 1H), 3.96 (d, J = 11.8 Hz, 1H), 3.83-3.72 (m, 2H), 1.84-1.73 (m, 1H), 1.70-1.62 (m, 1H), 1.56-1.50 (m, 1H), 1.50-1.42 (m, 2H), 1.39 (s, 3H), 1.39-1.37 (m, 3H), 1.36-1.30 (m, 1H), 1.23-1.13 (m, 1H), 1.04 (ddd, J = 4.4, 7.0, 9.0 Hz, 1H). Intermediate 45 (R)-4-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (int-45)

Step 1: A solution of (R)-2-amino-3-hydroxy-3-methylbutanoic acid (L-pentylamine) (1.492 g, 10 mmol, 1.0 equiv) in NaOH (1 M, 20 mL, 20 mmol, 2.0 equiv) was treated with _Boc2O (2.182 g, 10 mmol, 1.0 equiv) and dioxane (10 mL), and the biphasic solution was stirred at room temperature for 90 min. To the cloudy solution was added tert-butyl bromoacetate (1.951 g, 10 mmol, 1.0 equiv), and the resulting biphasic solution was stirred thoroughly at room temperature overnight. The mixture was diluted with water (150 mL), neutralized with 1 N HCl (11 mL), and extracted with EtOAc (5 x 40 mL). The combined organic extracts were washed once with water and once with brine, dried over MgSO ₄ , filtered and evaporated to give (R)-3-((2-(tert-butoxy)-2-oxoethyl)thio)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid. ¹ H NMR (500 MHz, CDCl ₃ ) δ 5.58 (d, J = 8.3 Hz, 1H), 4.31 (d, J = 8.1 Hz, 1H), 3.47 (d, J = 17.2 Hz, 1H), 3.34 (d, J = 17.0 Hz, 1H), 1.51-1.39 (m, 24H). MS (ESI): m / z 364.3 [M+H] ⁺ .

Step 2: A solution of crude (R)-3-((2-(tert-butoxy)-2-oxoethyl)thio)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (3.8 g, 10.45 mmol, 1.0 equiv) in THF (50 mL) was cooled to -10 °C, then _Et3N (1.594 mL, 11.50 mmol, 1.1 equiv) and isobutyl chloroformate (1.510 mL, 11.50 mmol, 1.1 equiv) were added. The resulting slurry was stirred at -10 °C for 30 min, then the solids were removed by filtration and the filter cake was washed with THF (2 x 5 mL). The filtrate was added dropwise to a stirred solution of _NaBH4 (1.187 g, 31.4 mmol, 3.0 equiv) in water (10 mL) between -10 °C and 0 °C over 10-15 min (gas evolution). After 5 min, the reaction was quenched with 1 N HCl (30 mL) (gas evolution), then the mixture was diluted with EtOAc (150 mL) and the layers were separated. The organic layer was washed once each with saturated _NaHCO3 and brine, then dried over _MgSO4 , filtered and evaporated to give crude (R)-tert-butyl 2-((3-((tert-butoxycarbonyl)amino)-4-hydroxy-2-methylbutan-2-yl)thio)acetate. MS (ESI): m / z 350.3 [M+H] ⁺ .

Step 3: A solution of crude (R)-tert-butyl 2-((3-((tert-butoxycarbonyl)amino)-4-hydroxy-2-methylbutan-2-yl)thio)acetate (3.8 g, 10.45 mmol, 1.0 equiv) was azeotroped once with toluene (25 mL), then the residue was redissolved in toluene (25 mL) and treated with 2,2-dimethoxypropane (6.43 mL, 52.3 mmol, 5.0 equiv) and p - _TsOH.H2O (0.099 g, 0.523 mmol, 0.05 equiv). The reaction was stirred at room temperature overnight, then concentrated and dried under high vacuum to give crude (R)-tert-butyl 4-(2-((2-(tert-butoxy)-2-oxoethyl)thio)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate. MS (ESI): m / z 390.3 [M+H] ⁺ .

Step 4: A mixture of crude (R)-tert-butyl 4-(2-((2-(tert-butoxy)-2-oxoethyl)thio)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (4.4 g, 10.45 mmol, 1.0 equiv) and _NaHCO3 (7.03 g, 84 mmol, 8.0 equiv) in acetone (30 mL) was cooled to 0°C, followed by the addition of ^Oxone® (14.46 g, 23.52 mmol, 2.25 equiv) and water (10 mL) (gas evolution). The resulting mixture was stirred at 0°C for 10 minutes, then at room temperature for 1 hour, then allowed to cool to 0°C and quenched _with 10% _Na2SO3 (15 mL). After 15 min at room temperature, the mixture was returned to the ice bath and neutralized with 1 N HCl (15 mL), then diluted with water (75 mL) and EtOAc (50 mL). The layers were separated, then the aqueous layer was extracted with EtOAc (4 x 25 mL). The combined organic extracts were washed with brine, dried over _MgSO4 , filtered, and concentrated to give (R)-tert-butyl 4-(2-((2-(tert-butoxy)-2-oxoethyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate. ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.59 (t, J = 8.3 Hz, 1H), 4.40 (dd, J = 30.2, 10.3 Hz, 1H), 4.12-4.01 (m, 1H), 3.94 (dd, J = 10.3, 5.7 Hz, 2H), 1.59 (s, 3H), 1.47 (dd, J = 24.1, 7.1 Hz, 28H). MS (ESI): m / z 422.2 [M+H] ⁺ .

Step 5: A solution of (R)-tert-butyl 4-(2-((2-(tert-butoxy)-2-oxoethyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (3.1 g, 7.35 mmol, 1.0 equiv) in DMF (15 mL) was treated with _K2CO3 (3.05 g, 22.06 mmol, 3.0 equiv) and 1,2-dibromoethane (1.267 mL, 14.71 mmol, 2.0 _equiv ) and the resulting mixture was stirred at 100 °C overnight. The reaction was diluted with water (150 mL) and extracted with EtOAc (4 × 40 mL), then the combined organic extracts were washed twice with 1:1 water-brine, once with brine, dried over _MgSO4 , filtered and concentrated to give crude (R)-tert-butyl 4-(2-((1-(tert-butoxycarbonyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate. ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.48 (d, J = 10.3 Hz, 1H), 3.97 (dd, J = 10.3, 6.0 Hz, 1H), 1.81-1.70 (m, 2H), 1.59 (d, J = 7.3 Hz, 6H), 1.51 (s, 6H), 1.48 (s, 18H), 1.44 (d, J = 4.5 Hz, 2H). MS (ESI): m / z 448.2 [M+H] ⁺ .

Step 6: A solution of crude (R)-tert-butyl 4-(2-((1-(tert-butoxycarbonyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (3.31 g, 7.35 mmol, 1.0 equiv) in THF (29 mL) was cooled to 0 °C and _LiAlH4 (1.0 M in THF, 14.71 mL, 14.71 mmol, 2.0 equiv) was added dropwise over 10-15 min (gas evolution). The resulting solution was stirred at 0 °C for 3 h and then quenched by the sequential addition of 0.6 mL of water (gas evolution), 1.2 mL of 2 N NaOH and 1.8 mL of water. The slurry was stirred at room temperature for 15 minutes, then _MgSO4 was added and the solids were removed by filtering through ^Celite® . The filter cake was washed with EtOAc and the filtrate was concentrated to give crude (R)-tert-butyl 4-(2-((1-(hydroxymethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate. ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.73 (d, J = 5.7 Hz, 1H), 4.45 (d, J = 10.2 Hz, 1H), 4.06 (dd, J = 13.9, 6.5 Hz, 1H), 4.01-3.93 (m, 2H), 3.81 (t, J = 6.7 Hz, 1H), 1.52-1.47 (m, 23H), 1.18 (dd, J = 10.0, 5.2 Hz, 1H), 1.13-1.08 (m, 1H). MS (ESI): m / z 378.3 [M+H] ⁺ .

Step 7: (R)-tert-butyl 4-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (int-45) was obtained using the method described in step 4 of the synthesis of intermediate (int-1), with the exception that (1-(cyclopropylsulfonyl)cyclopropyl)methanol (i1-c) was replaced with (R)-tert-butyl 4-(2-((1-(hydroxymethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate. MS (ESI): m / z 440.3 [M+H] ⁺ . Intermediate 46 7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-46)

Step 1: A solution of ethyl 2-oxoacetate (200 g, 980 mmol, 1.0 equiv) in THF (500 mL) was cooled to 0 °C, followed by the addition of 2-hydrazinoethanol (75 g, 980 mmol, 1.0 equiv). The reaction mixture was stirred at 25 °C for 12 h, then concentrated. The mixture was diluted with EtOAc (300 mL) and washed with water (2 x 100 mL), dried _over anhydrous _Na2SO4 , and concentrated under reduced pressure. The residue was purified by column chromatography ( _SiO2 , 75-100% EtOAc/petroleum ether) to give ethyl (E)-2-(2-(2-hydroxyethyl)hydrazono)acetate. TLC R _f = 0.3 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35 (br s, 1H), 6.79 (s, 1H), 4.29-4.21 (m, 2H), 3.89-3.86 (m, 2H), 3.39 (br s, 2H), 1.33-1.30 (m, 3H). MS (ESI): m / z 187.1 [M+H] ⁺ .

Step 2: To a solution of ethyl (E)-2-(2-(2-hydroxyethyl)hydrazono)acetate (50 g, 312 mmol, 1.0 eq) in DCM (500 mL) was added imidazole (85 g, 1248 mmol, 4.0 eq), DMAP (19 g, 156 mmol, 0.5 eq) and TIPSCl (120 g, 624 mmol, 2.0 eq). The mixture was stirred at 25 °C for 12 h and then washed with water (100 mL). The organic layer was dried _{over Na2SO4} , filtered and concentrated, and the residue was purified by column chromatography ( _SiO2 , 50-100% EtOAc/petroleum ether) to give ethyl (E)-2-(2-(2-((triisopropylsilyl)oxy)ethyl)hydrazono)acetate. TLC _Rf = 0.6 (75% EtOAc/petroleum ether). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.81-8.79 (m, 1H), 6.79 (s, 1H), 4.11-4.06 (m, 2H), 3.80-3.77 (m, 2H), 3.32-3.28 (m, 2H), 1.21-1.17 (m, 3H), 1.03-0.98 (m, 21H).

Step 3: A solution of ethyl (E)-2-(2-(2-((triisopropylsilyl)oxy)ethyl)hydrazono)acetate (35 g, 110.58 mmol, 1.0 equiv) in EtOAc (350 mL) was cooled to 0 °C, then NBS (21 g, 116.11 mmol, 1.05 equiv) was added portionwise. The reaction mixture was stirred at 25 °C for 0.5 h, then the solids were removed by filtration. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2 x 250 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , petroleum ether) to give ethyl (Z)-2-bromo-2-(2-(2-((triisopropylsilyl)oxy)ethyl)hydrazono)acetate. TLC R _f = 0.6 (1:10 EtOAc/petroleum ether). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.07-8.05 (m, 1H), 4.21-4.16 (m, 2H), 3.82-3.79 (m, 2H), 3.50-3.47 (m, 2H), 1.24-1.20 (m, 3H), 1.06-0.99 (m, 21H).

Step 4: A solution of 3-(N-morpholinyl)-5,6-dihydropyridin-2(lH)-one (14.66 g, 80.47 mmol, 1.0 equiv) and ethyl (Z)-2-bromo-2-(2-(2-((triisopropylsilyl)oxy)ethyl)hydrazono)acetate (35 g, 88.52 mmol, 1.1 equiv) in EtOAc (150 mL) was cooled to 0 °C and then _Et3N (20.82 g, 205.80 mmol, 2.6 equiv) was added. The mixture was stirred at 25 °C for 0.5 h and then at 80 °C for 1.5 h before the precipitate was removed by filtration. The filtrate was diluted with water (50 mL) and extracted with EtOAc (2 x 150 mL), then _the combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was suspended in 25% EtOAc/petroleum ether (30 mL) and stirred at 25 °C for 0.5 h, then the solid was collected by filtration. The filter cake was purified by RP-HPLC to give ethyl 7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-46). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.71 (br s, 1H), 4.83-4.80 (m, 2H), 4.45-4.40 (m, 2H), 4.11-4.09 (m, 2H), 3.59-3.55 (m, 2H), 3.13-3.09 (m, 2H), 1.42-1.39 (t, J = 7.1 Hz, 3H), 1.07-0.95 (m, 21H). MS (ESI): m / z 410.4 [M+H] ⁺ . Intermediate 47 1-(2-Hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-47)

Step 1: A solution of ethyl 2-oxoacetate (50% in toluene, 48 g, 233 mmol, 1.0 eq) in THF (210 mL) was cooled to 0 °C, followed by the addition of 1-hydrazinopropan-2-ol (21 g, 233 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 12 h, followed by concentration. The residue was diluted with EtOAc (300 mL) and washed with water (2 x 100 mL), followed by drying _{over Na2SO4} , filtering and concentration under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 75-100% EtOAc/petroleum ether) to give ethyl (E)-2-(2-(2-hydroxypropyl)hydrazono)acetate. TLC R _f = 0.3 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.16-7.11 (m, 1H), 6.81 (s, 1H), 4.29-4.23 (m, 2H), 4.13-4.10 (m, 1H), 3.37-3.33 (m, 1H), 3.17-3.15 (m, 1H), 1.33-1.29 (m, 3H), 1.26-1.24 (m, 3H).

Step 2: A solution of ethyl (E)-2-(2-(2-hydroxypropyl)hydrazono)acetate (6.3 g, 36.17 mmol, 1.0 equiv) in EtOAc (60 mL) was cooled to 0 °C, then NBS (6.76 g, 37.99 mmol, 1.05 equiv) was added portionwise. The reaction mixture was stirred at 25 °C for 0.5 h, then the precipitate was removed by filtration. The filtrate was diluted with water (10 mL) and extracted with EtOAc (2 x 50 mL), then the combined organic extracts were dried over _Na2SO4 , _filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , petroleum ether) to give ethyl (Z)-2-bromo-2-(2-(2-hydroxypropyl)hydrazono)acetate. TLC R _f = 0.6 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.09-6.91 (m, 1H), 4.35-4.30 (m, 2H), 4.08-4.05 (m, 1H), 3.61-3.57 (m, 1H), 3.42-3.36 (m, 1H), 1.36-1.32 (m, 3H), 1.22 (d, J = 6.4 Hz, 3H).

Step 3 A solution of 3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one (1.91 g, 10.47 mmol, 1.0 equiv) and ethyl (Z)-2-bromo-2-(2-(2-hydroxypropyl)hydrazono)acetate (5.30 g, 20.94 mmol, 2.0 equiv) in EtOAc (20 mL) was cooled to 0 °C, then _Et3N (2.65 g, 26.18 mmol, 2.5 equiv) was added. The mixture was stirred at 25 °C for 0.5 h, then at 80 °C for 1.5 h. The precipitate was removed by filtration, then the filtrate was diluted with water (8 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was purified by RP-HPLC to give 1-(2-hydroxypropyl ₎ -7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-47). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.78 (s, 1H), 4.69-4.66 (m, 1H), 4.61-4.58 (m, 1H), 4.46-4.40 (m, 2H), 4.28-4.17 (m, 1H), 3.64-3.60 (m, 2H), 3.17-3.13 (m, 2H), 1.43-1.39 (m, 3H), 1.27 (d, J = 6.4 Hz, 3H). MS (ESI): m / z 268.1 [M+H] ⁺ . Intermediate 48 Ethyl (Z)-2-chloro-2-(2-((1-hydroxycyclopropyl)methyl)hydrazono)acetate (int-48)

Step 1: A solution of methyl 1-hydroxycyclopropanecarboxylate (8 g, 68.9 mmol, 1.0 equiv) and hydrazine monohydrate (17 g, 344.4 mmol, 5.0 equiv) in MeOH (40 mL) was stirred at 60 °C for 16 h and then concentrated to give a solid. The resulting 8 g crude material was washed with EtOAc (10 mL) and dried in vacuo to give 1-hydroxycyclopropanecarboxylic acid hydrazide. TLC R _f = 0.4 (1:10 MeOH/EtOAc). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.04-8.78 (m, 1H), 6.09 (br s, 1H), 4.22 (br s, 2H), 1.04-0.97 (m, 2H), 0.85-0.78 (m, 2H).

Step 2: A solution of 1-hydroxycyclopropanecarboxylic acid hydrazide (4 g, 34.4 mmol, 1.0 equiv) in THF (40 mL) was cooled to 0 °C _{and BH3.SMe2} (34.4 mL, 344 mmol, 10.0 equiv) was added dropwise. The reaction was stirred at 60 °C for 16 h and then cooled to 0 °C and quenched by the slow addition of MeOH (50 mL) (gas evolution). The solids were removed by filtration and the filtrate was concentrated to give an oil. This material was dissolved in MeOH (50 mL) and heated at 80 °C for 5 h. The solution was concentrated to give crude 1-(hydrazinomethyl)cyclopropanol. TLC R _f = 0.8 (1:10 MeOH/EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 2.91 (s, 2H), 0.83 (t, J = 6.0 Hz, 2H), 0.55-0.50 (m, 2H).

Step 3: A mixture of ethyl-2-oxoacetate (8 g, 39.1 mmol, 1.0 eq), _Et3N (4 g, 39.1 mmol, 1.0 eq) and _MgSO4 (9.4 g, 78.3 mmol, 2.0 eq) in THF (40 mL) was cooled to 0 °C, followed by the addition of 1-(hydrazinomethyl)cyclopropanol (4 g, 39.1 mmol, 1.0 eq). The reaction mixture was stirred at 25 °C for 16 h, followed by removal of the solid by filtration and concentration of the filtrate under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 15-50% EtOAc/petroleum ether) to give ethyl (E)-2-(2-((1-hydroxycyclopropyl)methyl)hydrazono)acetate. TLC R _f = 0.7 (EtOAc). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.92 (br t, J = 4.2 Hz, 1H), 6.76 (s, 1H), 5.44 (s, 1H), 4.13-4.06 (m, 2H), 3.26 (d, J = 4.3 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H), 0.62-0.57 (m, 2H), 0.51-0.45 (m, 2H). MS (ESI): m / z 187.1 [M+H] ⁺ .

Step 4: A solution of (E)-ethyl 2-(2-((1-hydroxycyclopropyl)methyl)hydrazono)acetate (300 mg, 1.6 mmol, 1.0 equiv) in DMF (3 mL) was treated with NCS (236 mg, 1.77 mmol, 1.1 equiv) and the resulting mixture was stirred at 50 °C for 1 h. The reaction solution was diluted with water and extracted with EtOAc (5 mL), followed by back extraction of the aqueous layer with EtOAc (2 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried _{over Na2SO4} and concentrated. The residue was purified by column chromatography (SiO ₂ , 10-15% EtOAc/petroleum ether) to give ethyl (Z)-2-chloro-2-(2-((1-hydroxycyclopropyl)methyl)hydrazono)acetate (int-48). TLC R _f = 0.7 (75% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.84 (br s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 3.62 (d, J = 4.4 Hz, 2H), 2.88-2.32 (m, 1H), 1.36 (m, 3H), 0.91-0.86 (m, 2H), 0.69-0.64 (m, 2H). MS (ESI): m / z 221.0 [M+H] ⁺ . Intermediate 49 1-((1-Hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (int-49)

A solution of 3-(N-morpholinyl)-5,6-dihydropyridin-2(lH)-one (100 mg, 0.548 mmol, 1.0 equiv) and _Et3N (166 mg, 1.64 mmol, 3.0 equiv) in toluene (1 mL) was treated with ethyl (Z)-2-chloro-2-(2-((l-hydroxycyclopropyl)methyl)hydrazono)acetate (int-48) (130 mg, 0.589 mmol, 1.1 equiv) and the mixture was stirred at 110 °C for 12 h. The reaction was concentrated and the residue was purified by RP-HPLC (NH3.H2O) to give ethyl 1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-49). ¹ H NMR (400 MHz, _CDCl3 ) δ 5.76 (br s, 1H), 4.77 (s, 2H), 4.43 (m, 2H), 4.37 (br s, 1H), 3.63 (m, 2H), 3.16 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 0.89-0.76 (m, 4H). MS (ESI): m / z 280.0 [M+H] ⁺ . Intermediate 50 (Z)-2-chloro-2-(2-(2-hydroxy-2-methylpropyl)hydrazono)acetic acid ethyl ester (int-50)

Step 1: A mixture of sodium hydroxide (1 N, 12 drops) and hydrazine monohydrate (34.8 g, 695 mmol, 5.0 equiv) was treated with 2,2-dimethyloxirane (10 g, 139 mmol, 1.0 equiv) and the reaction was stirred at 95 °C for 16 hours. The hydrazine monohydrate was removed under reduced pressure and the residue was suspended in THF (16 mL) and MTBE (16 mL) and the precipitate was removed by filtration. The filtrate was concentrated to give 1-hydrazino-2-methylpropan-2-ol. TLC R _f = 0.3 (33% MeOH/CH ₂ Cl ₂ ). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.81 (br s, 1H), 3.22 (br s, 3H), 2.70 (s, 2H), 1.18 (s, 6H).

Step 2: Ethyl ( E )-2-(2-(2-hydroxy-2-methylpropyl)hydrazono)acetate. A mixture of ethyl 2-hydroxyacetate (5.88 g, 28.8 mmol, 1.0 eq.) and _MgSO4 (6.9 g, 57.6 mmol, 2.0 eq.) in THF (30 ml) was cooled to 0 °C, followed by the addition of 1-hydrazinyl-2-methylpropan-2-ol (3 g, 28.8 mmol, 1.0 eq.) and _Et3N (3.2 g, 31.7 mmol, 1.1 eq.). The reaction mixture was stirred at 25 °C for 12 h, then it was diluted with EtOAc (50 mL) and washed with water (3 x 20 mL). The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO ₂ , 30-100% EtOAc/petroleum ether) to give ethyl (E)-2-(2-(2-hydroxy-2-methylpropyl)hydrazono)acetate. TLC R _f = 0.5 (75% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.24 (br s, 1H), 6.80 (s, 1H), 4.27-4.21 (m, 2H), 3.23 (d, J = 4.4 Hz, 2H), 1.30-1.28 (m, 3H), 1.27 (s, 6H).

Step 3: Ethyl ( Z )-2-chloro-2-(2-(2-hydroxy-2-methylpropyl)hydrazono)acetate. A solution of ethyl (E)-2-(2-(2-hydroxy-2-methylpropyl)hydrazono)acetate (3.2 g, 17 mmol, 1.0 equiv) in DMF (20 mL) at 50 °C was treated with NCS (2.5 g, 18.7 mmol, 1.1 equiv) and stirred at 50 °C for 0.5 h. The mixture was diluted with water and extracted with EtOAc (2 x 30 mL), then the combined organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , 10-60% EtOAc/petroleum ether) to give ethyl (Z)-2-chloro-2-(2-(2-hydroxy-2-methylpropyl)hydrazono)acetate (int-50). TLC R _f = 0.5 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.91 (br s, 1H), 4.34-4.28 (m, 2H), 4.06 (s, 1H), 3.47 (d, J = 5.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H), 1.24 (s, 6H). Intermediate 51 1-(2-Hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-51)

To a solution of 3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one (1 g, 5.5 mmol, 1.0 equiv) in toluene (10 mL) was added _Et3N (1.67 g, 16.5 mmol, 3.0 equiv) and ethyl (Z)-2-chloro-2-(2-(2-hydroxy-2-methylpropyl)hydrazono)acetate (int-50) (1.5 g, 6.6 mmol, 1.2 equiv). The mixture was stirred at 120 °C for 6 h, then it was concentrated under reduced pressure. The mixture was diluted with water and extracted with EtOAc (2 x 30 mL), then _the combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was purified by RP-HPLC (FA) to give ethyl 1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-51). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.01 (br s, 1H), 4.63 (s, 2H), 4.44-4.39 (m, 2H), 3.63-3.59 (m, 2H), 3.14 (t, J = 6.8 Hz, 2H), 1.40 (t, J = 7.2 Hz, 3H), 1.24-1.22 (m, 6H). MS (ESI): m / z 282.2 [M+H] ⁺ . Intermediate 52 (Z)-2-bromo-2-(2-(3-hydroxypropyl)hydrazono)acetic acid ethyl ester (int-52)

Step 1: Ethyl 2-oxoacetate (11.32 g, 55.5 mmol, 1 eq) was dissolved in THF (50 ml) and 3-hydrazinopropan-1-ol (5.00 g, 55.5 mmol, 1 eq) was added to the solution at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (80 mL), washed with water (2 x 30 mL), dried _over anhydrous _Na2SO4 , filtered and concentrated in vacuo to give a crude residue. The residue was purified by silica gel chromatography to give ethyl (E)-2-(2-(3-hydroxypropyl)hydrazono)acetate. TLC _Rf = 0.3 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.19 (s, 1H), 6.73 (s, 1H), 4.30-4.23 (m, 2H), 3.79-3.76 (m, 2H), 3.39-3.35 (m, 2H), 1.92-1.86 (m, 2H), 1.31 (t, J = 7.1 Hz, 3H).

Step 2: Ethyl ( Z )-2-bromo-2-(2-(3-hydroxypropyl)hydrazono)acetate. A solution of ethyl (E)-2-(2-(3-hydroxypropyl)hydrazono)acetate (3.5 g, 20.09 mmol, 1.0 equiv) in EtOAc (35 mL) was cooled to 0 °C, followed by the slow addition of NBS (3.75 g, 21.09 mmol, 1.04 equiv). The reaction mixture was stirred at 25 °C for 0.5 h. The mixture was filtered, and the filtrate was diluted with water (5 mL) and extracted with EtOAc (2 x 30 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether) to give ethyl (Z)-2-bromo-2-(2-(3-hydroxypropyl)hydrazono)acetate (int-52). TLC R _f = 0.4 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.94 (s, 1H), 4.36-4.30 (m, 2H), 3.78-3.75 (m, 2H), 3.69-3.67 (m, 2H), 1.93-1.86 (m, 2H), 1.36-1.33 (m, 3H). Intermediate 53 1-(3-Hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-53)

Ethyl 1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate (int-53) was obtained using the method described for the synthesis of intermediate (int-51), with the exception that ethyl (Z)-2-chloro-2-(2-(2-hydroxy-2-methylpropyl)hydrazono)acetate (int-50) was replaced with ethyl (Z)-2-bromo-2-(2-(3-hydroxypropyl)hydrazono)acetate (int-52). ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.17 (s, 1H), 4.78-4.74 (m, 2H), 4.43-4.40 (m, 2H), 3.63-3.59 (m, 2H), 3.50-3.47 (m, 2H), 3.15-3.11 (m, 2H), 2.14-2.05 (m, 2H), 1.43-1.39 (m, 3H). MS (ESI): m / z 268.1 [M+H] ⁺ . Synthesis Example 1 of Exemplary Compounds N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (1)

A solution of 4-(aminomethyl)benzonitrile hydrochloride (81 mg, 0.48 mmol, 3.0 equiv) in toluene (1.2 mL) was cooled to 0 °C, then AlMe ₃ (1.0 M in toluene, 0.48 mL, 0.48 mmol, 3.0 equiv) was added dropwise, followed by ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-6) (50 mg, 0.16 mmol, 1.0 equiv) in one portion. After stirring the reaction at 60 °C for 2 h, it was cooled to 0 °C and quenched with water (1 mL). The mixture was extracted with EtOAc (3 x 1 mL) and the combined organic extracts were dried _{over Na2SO4} , filtered and concentrated. The crude material was purified by RP-HPLC to give N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (1). TLC _Rf = 0.3 (67% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74-7.59 (m, J = 8.3 Hz, 2H), 7.53-7.43 (m, J = 8.2 Hz, 2H), 7.35 (br t, J = 6.1 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 4.72 (d, J = 6.2 Hz, 2H), 4.58 (s, 2H), 4.38 (s, 3H), 2.39 (ddd, J = 3.1, 4.9, 8.0 Hz, 1H), 1.56-1.52 (m, 2H), 1.25-1.14 (m, 4H), 1.04-0.95 (m, 2H). MS (ESI): m/z 466.2 [M+H] ⁺ . Example 2 N- (4-cyanobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-6,7-dihydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (2)

N- (4-cyanobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-6,7-dihydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (2) was obtained using the procedure described in Example 1, except that intermediate (int-6) was replaced with intermediate (int-7). TLC R _f = 0.2 (67% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69-7.62 (m, J = 8.3 Hz, 2H), 7.53-7.44 (m, J = 8.3 Hz, 2H), 7.35 (br t, J = 6.2 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 4.72 (d, J = 6.2 Hz, 2H), 4.50 (s, 2H), 4.39 (s, 3H), 2.81 (s, 3H), 1.59-1.55 (m, 2H), 1.32-1.27 (m, 2H). MS (ESI): m/z 440.2 [M+H] ⁺ . Example 3 N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (3)

To a solution of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) (45 mg, 0.13 mmol, 1.0 equiv) and 4-(aminomethyl)benzonitrile hydrochloride (27 mg, 0.16 mmol, 1.2 equiv) in DMF (0.5 mL) was added T3P (248 mg, 0.39 mmol, 3.0 equiv) and DIPEA (84 mg, 0.65 mmol, 5.0 equiv). The reaction mixture was stirred at 25 °C for 2 h, then it was diluted with water (2 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was purified by RP-HPLC to give N-(4-cyanobenzyl ₎ -6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (3). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.30-7.28 (m, 1H), 4.65 (d, J = 6.4 Hz, 2H), 4.16 (s, 3H), 4.07 (s, 2H), 3.77-3.73 (m, 2H), 3.21-3.17 (m, 2H), 2.77-2.73 (m, 1H), 1.52-1.51 (m, 2H), 1.24-1.22 (m, 2H), 1.08-1.04 (m, 4H). MS (ESI): m / z 468.1 [M+H] ⁺ .

The compounds given in Table 1 below were prepared according to procedures similar to those described for compound (3) in Example 3. Table 1 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 4 N- (4-Chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 477.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.84 (t, J = 6.2 Hz, 1H), 7.38-7.30 (m, 4H), 4.37 (d, J = 6.4 Hz, 2H), 4.11 (s, 3H), 4.02 (s, 2H), 3.66 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 2.95-2.91 (m, 1H), 1.29-1.26 (m, 2H), 1.10-0.98 (m, 6H). 5 6-((1-(Cyclopropylsulfonyl)cyclopropyl)methyl) -N- (4-fluorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 461.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.82-8.79 (m, 1H), 7.35-7.31 (m, 2H), 7.15-7.10 (m, 2H), 4.37 (d, J = 6.4 Hz, 2H), 4.11 (s, 3H), 4.02 (s, 2H), 3.66 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 2.95-2.91 (m, 1H), 1.29-1.23 (m, 2H), 1.10-1.00 (m, 6H). 6 N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)- N ,1-dimethyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 482.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.83 (d, J = 7.2 Hz, 2H), 7.47-7.46 (m, 2H), 5.10 (s, 1H), 4.74 (s, 1H), 4.10 (s, 2H), 4.03-4.00 (m, 3H), 3.67-3.66 (m, 2H), 3.25 (s, 3H), 2.93-2.92 (m, 2H), 2.90-2.89 (m, 1H), 1.28 (s, 2H), 1.09-1.01(m, 6H). 7 N -((6-chloropyridin-3-yl)methyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 478.0 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 8.40 (d, J = 2.4 Hz, 1H), 7.70 (dd, J = 8.2, 2.5 Hz, 1H), 7.32 (d, J = 8.2 Hz, 1H), 7.26-7.22 (m, 1H), 4.61 (d, J = 6.3 Hz, 2H), 4.18 (s, 3H), 4.09 (s, 2H), 3.77 (t, J = 6.9 Hz, 2H), 3.21 (t, J = 6.9 Hz, 2H), 2.80-2.73 (m, 1H), 1.56-1.50 (m, 2H), 1.29-1.23 (m, 2H), 1.10 (dt, J = 7.8, 3.3 Hz, 2H), 1.08-1.05 (m, 2H). 8 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl- N- (4-methylbenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 457.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.70 (t, J = 6.3 Hz, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 7.9 Hz, 2H), 4.34 (d, J = 6.3 Hz, 2H), 4.11 (s, 3H), 4.02 (s, 2H), 3.66 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 2.94 (ddd, J = 12.8, 7.9, 5.0 Hz, 1H), 2.26 (s, 3H), 1.27 (q, J = 4.8 Hz, 2H), 1.12-0.97 (m, 6H). 9 N-(4-cyano-3-fluorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 486.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.98 (t, J = 6.2 Hz, 1H), 7.91-7.84 (m, 1H), 7.40 (d, J = 10.4 Hz, 1H), 7.35-7.30 (m, 1H), 4.47 (s, 2H), 4.13 (s, 3H), 4.02 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 2.97-2.91 (m, 1H), 1.30-1.25 (m, 2H), 1.11-1.07 (m, 2H), 1.07-0.98 (m, 4H). 10 N -((5-chlorothien-2-yl)methyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 483.0 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.90 (t, J = 6.2 Hz, 1H), 6.93 (d, J = 3.7 Hz, 1H), 6.84 (d, J = 3.7 Hz, 1H), 4.45 (d, J = 6.1 Hz, 2H), 4.11 (s, 3H), 4.02 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 3.00 (t, J = 6.8 Hz, 2H), 2.94 (ddd, J = 12.7, 7.8, 5.0 Hz, 1H), 1.27 (q, J = 4.8 Hz, 2H), 1.11-1.07 (m, 2H), 1.02 (ddd, J = 15.9, 6.6, 3.4 Hz, 4H). 11 N- (4-cyano-3-methylbenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 482.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.92 (t, J = 6.4 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.36 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 4.43 (d, J = 6.0 Hz, 2H), 4.13 (s, 3H), 4.03 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 3.03-2.91 (m, 3H), 2.46 (s, 3H), 1.32-1.25 (m, 2H), 1.12-0.98 (m, 6H). 12 N- (4-cyano-2-methylbenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 482.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) 8.87 (t, J = 6.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.37 (d, J = 8.0 Hz, 1H), 4.43 (d, J = 6.2 Hz, 2H), 4.14 (s, 3H), 4.03 (s, 2H), 3.68 (t, J = 6.8 Hz, 2H), 3.03-2.93 (m, 3H), 2.37 (s, 3H), 1.32-1.26 (m, 2H), 1.13-0.98 (m, 6H). 13 N- (4-cyano-2-fluorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 486.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.93 (t, J = 6.2 Hz, 1H), 7.83 (m, 1H), 7.67 (m, 1H), 7.50 (m, 1H), 4.50 (d, J = 6.0 Hz, 2H), 4.14 (s, 3H), 4.03 (s, 2H), 3.67 (m, 2H), 3.02-2.91 (m, 3H), 1.30-1.26 (m, 2H), 1.12-1.08 (m, 2H), 1.07-1.00 (m, 4H). 14 N -((5-cyanopyridin-2-yl)methyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 469.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.99-8.88 (m, 2H), 8.26 (dd, J = 2.4, 8.4 Hz, 1H), 7.49 (d, J = 8.2 Hz, 1H), 4.59 (d, J = 6.0 Hz, 2H), 4.15 (s, 3H), 4.04 (s, 2H), 3.68 (t, J = 6.8 Hz, 2H), 3.03-2.91 (m, 3H), 1.32-1.25 (m, 2H), 1.14-0.98 (m, 6H). 15 N- (4-cyano-3-methoxybenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 498.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.53 (d, J = 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 6.95 (s, 1H), 4.63 (d, J = 6.4 Hz, 2H), 4.17 (s, 3H), 4.08 (s, 2H), 3.93 (s, 3H), 3.76 (t, J = 6.8 Hz, 2H), 3.21 (t, J = 6.8 Hz, 2H), 2.82-2.71 (m, 1H), 1.56-1.49 (m, 2H), 1.28-1.21 (m, 2H), 1.13-1.00 (m, 4H). 16 ( S ) -N- (1-(4-cyanophenyl)ethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 482.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.61 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.12 (d, J = 7.6 Hz, 1H), 5.25 (m, 1H), 4.19 (s, 3H), 4.07 (m, 2H), 3.73 (m, 2H), 3.15 (m, 2H), 2.80-2.68 (m, 1H), 1.59 (d, J = 7.0 Hz, 3H), 1.54-1.48 (m, 2H), 1.29-1.21 (m, 2H), 1.11-1.06 (m, 2H), 1.06-1.01 (m, 2H). Chiral SFC separation conditions: OD-3_5CM_ETOH (DEA)_5_40_3ML_T35 column: Chiralcel OD-3 50×4.6mm ID, 3um mobile phase: 5% to 40% ethanol (0.05% DEA) in CO2, flow rate: 3 mL/min wavelength: 220 nm. SFC (C-07336-144-P2A_2, OD-3_5CM_ETOH(DEA)_5_40_3ML_T35.M): Rt=2.255, ee%=93.27 17 ( R ) -N- (1-(4-cyanophenyl)ethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 482.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.60 (m, 2H), 7.49 (d, J = 8.0 Hz, 2H), 7.12 (br d, J = 7.6 Hz, 1H), 5.25 (m, 1H), 4.19 (s, 3H), 4.07 (m, 2H), 3.77-3.69 (m, 2H), 3.15 (m, 2H), 2.75 (m, 1H), 1.59 (d, J = 7.0 Hz, 3H), 1.54-1.49 (m, 2H), 1.27-1.21 (m, 2H), 1.11-1.06 (m, 2H), 1.06-1.00 (m, 2H). SFC (OD-3_5CM_ETOH(DEA)_5_40_ 3ML_T35.M): Rt=1.729, ee%=100.00 18 ( R ) -N- (1-(4-chlorophenyl)-2-hydroxyethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 507.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 (d, J = 8.0 Hz, 1H), 7.41-7.34 (m, 4H), 5.02-4.94 (m, 2H), 4.14 (s, 3H), 4.02 (s, 2H), 3.74-3.62 (m, 4H), 2.98-2.89 (m, 3H), 1.30-1.25 (m, 2H), 1.11-1.06 (m, 2H), 1.06-0.99 (m, 4H). Chiral HPLC separation conditions: Column: Chiralcel OJ-3 50×4.6mm ID, 3um Mobile phase: 5% to 40% ethanol (0.05% DEA) in CO2 Flow rate: 3 mL/min Wavelength: 220 nm. SFC: Rt = 1.836, 91% ee, OJ-3_5CM_ETOH(DEA)_5_40_3ML_T35.M; 19 ( S ) -N- (1-(4-chlorophenyl)-2-hydroxyethyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 507.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 (d, J = 8.0 Hz, 1H), 7.37 (m, 4H), 5.01-4.94 (m, 2H), 4.14 (s, 3H), 4.02 (s, 2H), 3.69-3.63 (m, 4H), 2.97-2.91 (m, 3H), 1.27-1.26 (m, 2H), 1.08-1.06 (m, 2H), 1.04-1.00 (m, 4H). SFC: Rt = 1.683, 100% ee, OJ-3_5CM_ETOH(DEA)_5_40_3ML_T35.M; 20 N- (4-cyanobenzyl)-6-((1-(ethylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 456.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.31-7.28 (m, 1H), 4.66 (d, J = 6.3 Hz, 2H), 4.17 (s, 3H), 3.96 (s, 2H), 3.75 (t, J = 6.9 Hz, 2H), 3.27 (q, J = 7.4 Hz, 2H), 3.20 (t, J = 6.9 Hz, 2H), 1.57-1.51 (m, 2H), 1.42 (t, J = 7.5 Hz, 3H), 1.08-1.02 (m, 2H). twenty one N- (4-cyanobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 442.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (t, J = 6.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.46 (d, J = 6.4 Hz, 2H), 4.12 (s, 3H), 3.96 (s, 2H), 3.66 (t, J = 7.0 Hz, 2H), 3.11 (s, 3H), 2.98 (t, J = 6.8 Hz, 2H), 1.30-1.27 (m, 2H), 1.11-1.10 (m, 2H). twenty two N- (4-Chlorobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 451.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85 (t, J = 6.2 Hz, 1H), 7.38-7.30 (m, 4H), 4.37 (d, J = 6.4 Hz, 2H), 4.11 (s, 3H), 3.96 (s, 2H), 3.66 (t, J = 6.8 Hz, 2H), 3.11 (s, 3 H), 2.99 (t, J = 6.8 Hz, 2 H), 1.30-1.27 (m, 2 H), 1.11-1.08 (m, 2 H). twenty three N- (4-cyano-3-fluorobenzyl)-1-methyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 460.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.62-7.58 (m, 1H), 7.35-7.31 (m, 1H), 7.25-7.20 (m, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.18 (s, 3H), 3.98 (s, 2H), 3.78-3.75 (m, 2H), 3.22-3.18 (m, 2H), 3.08 (s, 3H), 1.58-1.55 (m, 2H), 1.10-1.07 (m, 2H). Example 24 4-Cyanobenzyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (24)

A solution of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) (100 mg, 0.283 mmol, 1.0 equiv), 4-(hydroxymethyl)benzonitrile (57 mg, 0.424 mmol, 1.5 equiv) and _PBu3 (86 mg, 0.424 mmol, 1.5 equiv) in THF (1 mL) was cooled to 0 °C, followed by the addition of di-tert-butyl azodicarboxylate (DTBAD) (98 mg, 0.424 mmol, 1.5 equiv). After 1 h at 25 °C, the reaction mixture was concentrated and the residue was purified by RP-HPLC. The resulting material was triturated with MTBE to afford 4-cyanobenzyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (24). ¹ H NMR (400 MHz, CDCl ₃ ,) δ 7.68 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 5.43 (s, 2H), 4.25 (s, 3H), 4.07 (s, 2H), 3.77 (m, 2H), 3.12 (m, 2H), 2.82-2.61 (m, 1H), 1.56-1.49 (m, 2H), 1.30-1.20 (m, 2H), 1.14-0.99 (m, 4H). MS (ESI): m / z 469.4 [M+H] ⁺ . Example 25 4-(2-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-2-oxoethoxy)benzonitrile (25)

Step 1: 3-(2-Chloroacetyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-1,4,5,6-tetrahydro- 7H -pyrazolo[3,4- c ]pyridin-7-one. To a mixture of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) (235 mg, 0.665 mmol, 1.0 equiv) in ethylenediamine chloride (1.1 mL, 13.3 mmol, 20 equiv) was added DMF (10.3 µL, 0.132 mmol, 0.2 equiv) at room temperature. After 3 h, the reaction was concentrated and the crude residue was dissolved in 1:1 THF-MeCN (2 mL) and cooled to 0 °C. A solution of _TMSCHN2 (2.0 M in hexanes, 665 µL, 1.33 mmol, 2.0 equiv) and _Et3N (184 µL, 1.33 mmol, 2.0 equiv) was added dropwise. The mixture was stirred at 0 °C for 2 h, then HCl (4.0 M in _Et2O , 8.7 mL, 34.8 mmol, 52 equiv) was added. The mixture was stirred at 0 °C for 1 h, then it _was partitioned between saturated _NaHCO3 (100 mL) and _CH2Cl2 (200 mL). The layers were separated and the aqueous layer was extracted _{with CH2Cl2} (100 mL) and the combined organic extracts were dried _{over Na2SO4} , filtered and concentrated. The residue was purified by column chromatography ( _SiO2 , 0-100 % EtOAc/heptane) to give 3-(2-chloroacetyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one. ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.79 (s, 2H), 4.22 (s, 3H), 4.07 (s, 2H), 3.76 (t, J = 6.9 Hz, 2H), 3.17 (t, J = 6.9 Hz, 2H), 2.81 - 2.69 (m, 1H), 1.53 - 1.50 (m, 2H), 1.29 - 1.20 (m, 2H), 1.11 - 1.06 (m, 2H), 1.06 - 1.00 (m, 2H), 0.88 (t, J = 6.7 Hz, 1H). MS (ESI): m/z 386.1 [M+H] ⁺ .

Step 2: 4-(2-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-2-oxoethoxy)benzonitrile (25). 3-(2-Chloroacetyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (12 mg, 31 µmol, 1.0 equiv), K ₂ CO ₃ (6.45 mg, 47 µmol, 1.5 equiv) and 4-hydroxybenzonitrile (5.56 mg, 47 A mixture of 10 μL (20 μmol, 1.5 equiv) in MeCN (311 μL) was heated at 60 °C for 14 h and then concentrated. The residue was partitioned between EtOAc (2 mL) and H ₂ O (2 mL), the layers were separated, and the aqueous layer was then extracted with EtOAc (3 × 5 mL). The combined organic extracts were dried over MgSO ₄ , filtered, and concentrated. The residue was purified by column chromatography ( _SiO2 , 0-100 % EtOAc/heptane) to afford 4-(2-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-2-oxoethoxy)benzonitrile (25). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.59 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 5.41 (s, 2H), 4.24 (s, 3H), 4.07 (s, 2H), 3.76 (t, J = 6.9 Hz, 2H), 3.16 (t, J = 6.9 Hz, 2H), 2.78 (tt, J = 8.3, 4.8 Hz, 1H), 1.54 - 1.50 (m, 2H), 1.26 - 1.21 (m, 3H), 1.11 - 1.06 (m, 2H), 1.05 - 1.02 (m, 2H). MS (ESI): m/z 469.2 [M+H] ⁺ . Example 26 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)benzonitrile (26)

Step 1: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. To a solution of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) (300 mg, 0.849 mmol, 1.0 equiv), HOBt (345 mg, 2.55 mmol, 3.0 equiv), EDCI (489 mg, 2.55 mmol, 3.0 equiv) in DMF (2 mL) was added NH _{2 O} dropwise at 25 °C. A solution of _NH2 · _H2O (425 mg, 8.49 mmol, 10 equiv) in DMF (1 mL). The mixture was stirred at 25 °C for 2 h, then filtered and purified by RP-HPLC to give 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxyhydrazide.

Step 2: N '-(2-(4-cyanophenyl)acetyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid hydrazide was obtained using the procedure detailed in step 1, with the exceptions that (int-11) was replaced with 2-(4-cyanophenyl)acetic acid and hydrazine was replaced with 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid hydrazide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.02-8.85 (m, 1H), 8.26 (br s, 1H), 7.65 (m, 2H), 7.53-7.43 (m, 2H), 4.17 (s, 3H), 4.06 (s, 2H), 3.78-3.74 (m, 2H), 3.74 (s, 2H), 3.14 (m, 2H), 2.80-2.67 (m, 1H), 1.56-1.49 (m, 2H), 1.25-1.21 (m, 2H), 1.12-1.01 (m, 4H). MS (ESI): m/z 511.2 [M+H] ⁺ .

Step 3: 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)benzonitrile (26). N '-(2-(4-cyanophenyl)acetyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid hydrazide (140 mg, 0.27 mmol, 1.0 equiv) and pyridine (100 µL, 1.1 To a solution of 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)benzonitrile (26) was added _Tf2O (140 µL, 0.82 mmol, 3.0 equiv). After stirring at room temperature for 2 h, the mixture was concentrated and purified by RP-HPLC to give 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1,3,4-oxadiazol-2-yl)methyl)benzonitrile (26). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.69-7.61 (m, 2H), 7.48 (d, J = 8.4 Hz, 2H), 4.35 (s, 2H), 4.26 (s, 3H), 4.11-4.07 (m, 2H), 3.85-3.79 (m, 2H), 3.21 (m, 2H), 2.77 (m, 1H), 1.56-1.51 (m, 2H), 1.26-1.22 (m, 2H), 1.11-1.05 (m, 4H). MS (ESI): m/z 493.2 [M+H] ⁺ . Example 27 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1,2,4-oxadiazol-3-yl)methyl)benzonitrile (27)

Step 1: ( Z )-2-(4-bromophenyl)-N ' -((6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbonyl)oxy)acetamidine was obtained using the procedure detailed in Example 26, Step 1, except that hydrazine was replaced with (Z)-2-(4-bromophenyl)-N'-hydroxyacetamidine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.49 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 4.97-4.73 (m, 1H), 4.86 (br s, 1H), 4.23 (s, 3H), 4.08 (s, 2H), 3.78 (m, 2H), 3.61 (s, 2H), 3.19 (m, 2H), 2.77-2.68 (m, 1H), 1.54-1.52 (m, 2H), 1.27-1.23 (m, 2H), 1.12-1.04 (m, 4H). MS (ESI): m/z 564.2 [M+H] ⁺ .

Step 2: 3-(3-(4-Bromobenzyl)-1,2,4-oxadiazol-5-yl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4- c ]pyridin-7( 4H )-one. ( Z )-2-(4-Bromophenyl)-N ' -((6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbonyl)oxy)acetamidine (244 mg, 446 µmol, 1.0 equiv) and _Et3N (223 µL, 2.23 mmol, 5.0 equiv) in dioxane (5 mL) was stirred at 80 °C for 12 h, then diluted with _H2O (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried _{over Na2SO4} , filtered and concentrated. Purification by RP-HPLC gave 3-(3-(4-bromobenzyl)-1,2,4-oxadiazol-5-yl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4- c ]pyridin-7( 4H )-one. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.45 (d, J = 8.3 Hz, 2H), 7.25 (s, 2H), 4.28 (s, 3H), 4.13-4.06 (m, 4H), 3.82 (t, J = 6.8 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H), 2.79-2.68 (m, 1H), 1.56-1.52 (m, 2H), 1.29-1.22 (m, 3H), 1.12-1.04 (m, 4H). MS (ESI): m/z 546.0 [M+H] ⁺ .

Step 3: 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1,2,4-oxadiazol-3-yl)methyl)benzonitrile (27). 3-(3-(4-bromobenzyl)-1,2,4-oxadiazol-5-yl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one (50 mg, 0.092 mmol, 1.0 equiv) in dioxane (1 mL) and H ₂ O (0.2 To a mixture of 50 mL (10 mL) was added XPhos (15 mg, 0.036 mmol, 0.4 eq), K ₄ Fe(CN) ₆ (101 mg, 0.275 mmol, 3.0 eq), K ₂ CO ₃ (40 mg, 0.275 mmol, 3.0 eq) and Pd(OAc) ₂ (4 mg, 0.018 mmol, 0.2 eq). The reaction mixture was degassed and placed under N ₂ , then stirred at 120 °C for 12 h. The mixture was filtered and purified by RP-HPLC to give 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1,2,4-oxadiazol-3-yl)methyl)benzonitrile (27). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 4.28 (s, 3H), 4.21 (s, 2H), 4.09 (s, 2H), 3.83 (m, 2H), 3.19 (m, 2H), 2.78-2.70 (m, 1H), 1.55-1.53 (m, 2H), 1.28-1.22 (m, 2H), 1.13-1.05 (m, 4H). MS (ESI): m/z 493.2 [M+H] ⁺ . Example 28 4-((3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)benzonitrile (28)

Step 1: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. To a solution of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) (300 mg, 0.85 mmol, 1.0 equiv) and HATU (970 mg, 2.55 mmol, 3.0 equiv), DIEA (1097 mg, 8.49 mmol, 10.0 equiv) in DMF (3 mL) was added NH ₄ Cl (227 The reaction mixture was stirred at 25 °C for 2 h, then filtered and purified by RP-HPLC to give 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.71 (br s, 1H), 5.42 (br s, 1H), 4.18 (s, 3H), 4.08 (s, 2H), 3.78-3.71 (m, 2H), 3.21-3.15 (m, 2H), 2.79-2.69 (m, 1H), 1.55-1.48 (m, 2H), 1.27-1.22 (m, 2H), 1.12-1.02 (m, 4H). MS (ESI): m/z 353.1 [M+H] ⁺ .

Step 2: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbonitrile. To a solution of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (220 mg, 0.62 mmol, 1.0 equiv) in THF (2.5 mL) were added pyridine (0.13 mL, 1.56 mmol, 2.5 equiv) and TFAA (0.1 mL, 1.56 mmol, 2.5 equiv). The reaction mixture was stirred at 25 °C for 12 h and then concentrated. Purification by RP-HPLC gave 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.22 (s, 3H), 4.12-3.98 (m, 2H), 3.81 (m, 2H), 2.99 (m, 2H), 2.74 (m, 1H), 1.55-1.51 (m, 2H), 1.28-1.21 (m, 2H), 1.13-1.01 (m, 4H). MS (ESI): m/z 335.1 [M+H] ⁺ .

Step 3: ( Z )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl) -N' -hydroxy-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboximidamide. To a solution of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (90 mg, 0.27 mmol, 1.0 equiv) in EtOH (1.5 mL) was added _NH2OH ·HCl (28 mg, 0.32 mmol, 1.2 equiv) and _Et3N (82 mg, 0.81 mmol, 3.0 equiv). The reaction mixture was heated at 80 °C for 2 h, then concentrated and purified by RP-HPLC to give (Z)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-N'-hydroxy-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboximidamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 6.52 (br s, 1H), 5.17 (s, 2H), 4.16 (s, 3H), 4.08 (s, 2H), 3.72 (m, 2H), 3.02 (m, 2H), 2.75-2.66 (m, 1H), 1.53-1.49 (m, 2H), 1.27-1.22 (m, 2H), 1.11-1.04 (m, 4H). MS (ESI): m/z 368.1 [M+H] ⁺ .

Step 4: 4-((3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)benzonitrile (28). ( Z )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl) -N' -hydroxy-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboximidamide (60 mg, 0.163 mmol, 1.0 equiv), CDI (79 mg, 0.490 mmol, 3.0 equiv) and Et To a solution of ₃ N (66 mg, 0.653 mmol, 4.0 equiv) in DCE (0.6 mL) was added 2-(4-cyanophenyl)acetic acid (53 mg, 0.327 mmol, 2.0 equiv). The reaction mixture was stirred at 25 °C for 2 h, then it was heated at 80 °C for 4 h. The mixture was diluted with _H2O (5 _mL ) and extracted with _CH2Cl2 (4 x 5 mL), then the combined organic extracts were dried _{over Na2SO4} , filtered, and concentrated. The residue was purified by RP-HPLC to give 4-((3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1,2,4-oxadiazol-5-yl)methyl)benzonitrile (28). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.38 (s, 2H), 4.27 (s, 3H), 4.10 (s, 2H), 3.81 (m, 2H), 3.15 (m, 2H), 2.77-2.69 (m, 1H), 1.54-1.52 (m, 2H), 1.28-1.23 (m, 2H), 1.13-1.06 (m, 4H). MS (ESI): m/z 493.2 [M+H] ⁺ . Example 29 and Example 30 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl) -2H -tetrazol-2-yl)methyl)benzonitrile (29) and 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1H - tetrazol-1-yl)methyl)benzonitrile (30)

Step 1: 6-((1-(Cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-3-( 2H -tetrazol-5-yl)-1,4,5,6-tetrahydro- 7H -pyrazolo[3,4- c ]pyridin-7-one. 6-((1-(Cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (see Example 28, Step 2) (140 mg, 0.42 mmol, 1.0 equiv), NaN ₃ (90 mg, 1.38 mmol, 3.3 equiv) and NH ₄ Cl (82 mg, 1.26 mmol, 3.0 equiv) were dissolved in DMF (2% MgSO 4 ). The mixture was heated at 100°C for 3 hours in 5% paraformaldehyde (2% paraformaldehyde) (2% paraformaldehyde) (3% paraformaldehyde) (4% paraformaldehyde) (5% paraformaldehyde) (6% paraformaldehyde) (2% paraformaldehyde) (3% paraformaldehyde) (4 ...4% paraformaldehyde) (4% paraformaldehyde) (4% paraformaldehyde) (4% paraformaldehyde) (4 ¹ H NMR (400 MHz, CDCl ₃ ) δ 3.92 (s, 3H), 3.87 (br s, 2H), 3.42 (br s, 2H), 2.90 (br s, 2H), 2.84 (s, 1H), 2.79-2.69 (m, 1H), 1.37-1.21 (m, 2H), 1.16-1.06 (m, 2H), 1.00 (br d, J = 7.0 Hz, 2H), 0.88 (br s, 2H). MS (ESI): m/z 378.1 [M+H] ⁺ .

Step 2: 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-2H- tetrazol -2-yl)methyl)benzonitrile (29) and 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1H - tetrazol-1-yl)methyl)benzonitrile (30). A mixture of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-3-(2H-tetrazol-5-yl)-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-c]pyridin-7-one (120 mg, 0.32 mmol, 1.0 equiv), 4-(bromomethyl)benzonitrile (125 mg, 0.64 mmol, 2.0 equiv) and _K2CO3 (132 mg, 0.96 mmol, 3.0 equiv) in DMF (2 _mL ) was stirred at room temperature for 1 h. The reaction mixture was filtered and purified by RP-HPLC and SFC to give: 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl) -2H -tetrazol-2-yl)methyl)benzonitrile (29): ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.89 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.9 Hz, 2H), 6.13 (s, 2H), 4.14 (s, 3H), 4.05 (s, 2H), 3.73 (t, J = 6.9 Hz, 2H), 3.06 (t, J = 6.7 Hz, 2H), 2.94 (s, 1H), 1.29 (s, 2H), 1.11 (s, 2H), 1.08-1.00 (m, 4H). MS (ESI): m/z 493.1 [M+H] ⁺ . and 4-((5-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1H - tetrazol-1-yl)methyl)benzonitrile (30): ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.83 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 6.15 (s, 2H), 4.17 (s, 3H), 4.06 (s, 2H), 3.76 (t, J = 6.8 Hz, 2H), 3.12 (t, J = 6.8 Hz, 2H), 2.95 (ddd, J = 12.7, 7.8, 4.9 Hz, 1H), 1.32-1.26 (m, 2H), 1.15-1.09 (m, 2H), 1.09-0.98 (m, 4H). MS (ESI): m/z 493.2 [M+H] ⁺ . Example 31 4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (31)

Step 1: 6-((1-(Cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxaldehyde. A solution of ethyl 6-((1-(Cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate (int-12) (600 mg, 1.57 mmol, 1.0 equiv) in THF (10 mL) was cooled to -70 °C, followed by the addition of DIBAL-H (1.0 M in THF, 4.72 mL, 4.72 mmol, 3.0 equiv) dropwise. After 2 h at -70 °C, MeOH (10 mL) was added and the reaction mixture was allowed to warm to room temperature. The solution was diluted with _H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were dried _{over Na2SO4} , filtered, and concentrated to give crude 4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile. MS (ESI): m/z 338.3 [M+H] ⁺ .

Step 2: ( E )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbaldehyde oxime. To a solution of _NH2OH ·HCl (151 mg, 1.42 mmol, 1.2 eq) in MeOH (5 mL) was added _Na2CO3 (302 _mg , 2.85 mmol, 2.4 eq) followed by 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbaldehyde (400 mg, 1.19 mmol, 1.0 equiv) in MeOH (10 mL). The mixture was stirred at 20 °C for 3 h, then poured into _H2O (5 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were dried _{over Na2SO4} , filtered, and concentrated to give crude ( E )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbaldehyde oxime. MS (ESI): m/z 353.3 [M+H] ⁺ .

Step 3: ( Z )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl) -N -hydroxy-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboimidyl chloride . To a solution of ( E )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbaldehyde oxime (400 mg, 1.14 mmol, 1.0 equiv) in DMF (8 mL) was added NCS (159 mg, 1.19 mmol, 1.0 equiv) portionwise. The mixture was stirred at 20 °C for 1 h, then poured into _H2O (8 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried _{over Na2SO4} , filtered, and concentrated to give ( Z )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl) -N -hydroxy-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboimidyl chloride. MS (ESI): m/z 387.0 [M+H] ⁺ .

Step 4: 4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (31). ( Z )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl) -N -hydroxy-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboimidyl chloride (400 mg, 1.03 mmol, 1.0 equiv) and 4-vinylbenzonitrile (200 mg, 1.55 To a solution of 4-(4-( _4- ( ₄ -piperidin-2-yl) _-1 -nitropropene) ( ₂ ... The residue was purified by column chromatography ( _SiO2 , 10-100 % EtOAc/petroleum ether) to give 4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (31). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.77-7.60 (m, 2H), 7.51-7.42 (m, 2H), 5.74-5.70 (m, 1H), 4.15 (s, 3H), 4.10-4.05 (m, 2H), 3.90 (dd, J = 11.1, 17.2 Hz, 1H), 3.77 (t, J = 6.8 Hz, 2H), 3.42-3.40 (m, 1H), 3.13-3.09 (m, 2H), 2.75-2.73 (m, 1H), 1.55 (s, 2H), 1.54-1.47 (m, 2H), 1.27-1.20 (m, 3H), 1.12 (br s, 1H), 1.12-1.01 (m, 3H). MS (ESI): m/z 480.1 [M+H] ⁺ . Example 32 and Example 33 ( R ) -4- (3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H- pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (32) and ( S )-4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro -1H- pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (33)

( R ) -4- (3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H- pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (32) and ( S )-4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro -1H- pyrazolo[3,4- c]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (32) ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (33) was obtained by chiral SFC of 4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (31). (OJ-3_MeOH+ACN(DEA)_40_3mL-35T column: Chiralcel OJ-3 50×4.6mm ID, 3um mobile phase: 40% methanol in _CO2 +ACN(0.05% DEA) flow rate: 3mL/min wavelength: 220nm). (R)-4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (32): Rt = 1.31 min, >99% ee, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68 (d, J = 8.4, 2H), 7.50 (d, J = 8.4 Hz, 2H), 5.75-5.71 (m, 1H), 4.16 (s, 3H), 4.09 (s, 2H), 3.91-3.86 (m, 1H), 3.78 (t, J = 6.8 Hz, 2H), 3.43-3.90 (m, 1H), 3.12 (t, J = 6.8 Hz, 2H), 2.76-2.73 (m, 1H), 1.56-1.49 (m, 2H), 1.29-1.21 (m, 2H), 1.13-1.03 (m, 4H). MS (ESI): m/z 480.1 [M+H] ⁺ .

(S )-4-(3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro -1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (33): Rt = 0.993 min, 99% ee, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 5.75-5.70 (m, 1H), 4.16 (s, 3H), 4.09 (s, 2H), 3.93-3.86 (m, 1H), 3.78 (t, J = 6.8 Hz, 2H), 3.48-3.33 (m, 1H), 3.12 (t, J = 6.8 Hz, 2H), 2.81-2.70 (m, 1H), 1.58-1.48 (m, 2H), 1.29-1.20 (m, 2H), 1.12-1.00 (m, 4H). MS (ESI): m/z 480.1 [M+H] ⁺ . Example 34 4-((3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)isoxazol-5-yl)methyl)benzonitrile (34)

Step 1: 3-(5-(4-bromobenzyl)isoxazol-3-yl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4-c]pyridin-7( 4H )-one. (Z)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-N-hydroxy-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboimidyl chloride (see Example 31, Step 3) (500 mg, 1.29 mmol, 1.0 equivalent), 1-bromo-4-(prop-2-yn-1-yl)benzene (378 A mixture of _4- pyridine - ₂ -yl ( _4- pyridine- ₂ -yl) - ... The residue was purified by column chromatography (SiO ₂ , 10-100 % EtOAc/petroleum ether) to give 3-(5-(4-bromobenzyl)isoxazol-3-yl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4-c]pyridin-7( 4H )-one. MS (ESI): m/z 547.1 [M+H] ⁺ .

Step 2: 4-((3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c [0367] benzonitrile (34) was obtained using the procedure described in Example 27, Step 3, except that 3-(3-(4-bromobenzyl)-1,2,4-oxadiazol-5-yl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one was replaced with 3-(5-(4-bromobenzyl)isoxazol-3-yl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4-c]pyridin-7( 4H )-one. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.2 Hz, 2H), 6.41 (s, 1H), 4.20 (s, 5H), 4.11-4.05 (m, 2H), 3.82-3.73 (m, 2H), 3.15 (t, J = 6.8 Hz, 2H), 2.76-2.69 (m, 1H), 1.55-1.46 (m, 2H), 1.29-1.17 (m, 2H), 1.14-1.02 (m, 4H). MS (ESI): m/z 492.4 [M+H] ⁺ . Example 35 4-((4-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl) -1H- 1,2,3-triazol-1-yl)methyl)benzonitrile (35)

Step 1: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-ethynyl-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4- c ]pyridin-7( 4H )-one. To a solution of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbaldehyde (see Example 31, Step 1) (450 mg, 1.33 mmol, 1.0 equiv) and dimethyl (1-diazo-2-oxopropyl)phosphonate (384 mg, 2.00 mmol, 1.5 equiv) in MeOH (10 mL) was added _K2CO3 at 20°C. ₃ (369 mg, 2.67 mmol). The mixture was stirred at 20 °C for 12 h, then poured into H ₂ O (10 mL) and extracted with EtOAc (3 × 10 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated to give 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-ethynyl-1-methyl-5,6-dihydro-1H-pyrazolo[3,4-c]pyridin-7(4H)-one. TLC R _f = 0.5 (50% EtOAc/petroleum ether). MS (ESI): m/z 334 [M+H] ⁺ .

Step 2: 4-((4-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1H - 1,2,3-triazol-1-yl)methyl)benzonitrile (35). 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-ethynyl-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4- c ]pyridin-7( 4H )-one (350 mg, 1.05 mmol, 1.0 equiv), 4-(azidomethyl)benzonitrile (332 mg, 2.10 mmol, 2.0 equiv), _CuSO4 · _5H2 A mixture of 4-(4-(4-hydroxy-1-yl) _-2 -nitropropene (3-[4-(4-nitropropene)-1-yl)-4-nitropropene (3-[4-(4-hydroxy-1-yl)-2-nitropropene) (3-[4-hydroxy-1-yl)-2-nitropropene) (3-[4-hydroxy-1-yl)-2-nitropropene) (3-[4-hydroxy-1-yl)-2-nitropropene) (3-[4-hydroxy-1-yl)-2-nitropropene) (3-[4-hydroxy-1-yl)-2-nitropropene) (3-[4-hydroxy-1-yl)-2-nitropropene) (3-[4-hydroxy-1-yl)-2-nitropropene) (3-[ ₄ -hydroxy-1-yl)-2-nitropropene) (3-[4-hydroxy- _1- yl)-2-nitropropene) ( The residue was purified by RP-HPLC to give 4-((4-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl) -1H -1,2,3-triazol-1-yl)methyl)benzonitrile (35). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.56 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 5.82-5.71 (m, 2H), 4.09 (s, 3H), 4.05 (s, 2H), 3.73 (t, J = 6.8 Hz, 2H), 3.06 (t, J = 6.8 Hz, 2H), 3.01-2.90 (m, 1H), 1.35-1.26 (m, 2H), 1.15-1.09 (m, 2H), 1.08-0.98 (m, 4H). MS (ESI): m/z 492.2 [M+H] ⁺ . Example 36 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(1-((4,4-difluorocyclohexyl)methyl)-1H - 1,2,3-triazol-4-yl)-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4- c ]pyridin-7( 4H )-one (36)

6-((1-(Cyclopropylsulfonyl)cyclopropyl)methyl)-3-(1-((4,4-difluorocyclohexyl)methyl)-1H - 1,2,3-triazol-4-yl)-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4- c ]pyridin-7( 4H )-one (36) was obtained using the procedure described in Example 35, Step 2, except that 4-(azidomethyl)benzonitrile was replaced with 4-(azidomethyl)-1,1-difluorocyclohexane. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 7.86 (s, 1H), 4.30 (d, J = 7.2 Hz, 2H), 4.20 (s, 3H), 4.11 (s, 2H), 3.80 (t, J = 6.8 Hz, 2H), 3.28 (t, J = 6.8 Hz, 2H), 2.78-2.67 (m, 1H), 2.20-2.05 (m, 3H), 1.83-1.70 (m, 3H), 1.55-1.48 (m, 2H), 1.47-1.35 (m, 2H), 1.30-1.21 (m, 2H), 1.15-1.04 (m, 4H). MS (ESI): m/z 509.4 [M+H] ⁺ . Example 37 N- (4-chlorophenoxy)-1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (37)

N- (4-chlorophenoxy)-1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (37) was obtained using the procedure described in Example 28, step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-14) and NH ₄ Cl was replaced with O-(4-chlorophenyl)hydroxylamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 9.57 (s, 1H), 7.28 (s, 2H), 7.26-7.25 (m, 2H), 7.11-7.08 (m, 2H), 4.20 (s, 3H), 4.13 (s, 2H), 3.72 (m, 2H),3.17 (m, 2H), 1.62 (s, 3H), 1.55-1.52 (m, 2H), 1.47 (m, 2H), 1.05-1.03 (m, 2H),0.88-0.86 (m, 2H). MS (ESI): m/z 493.1 [M+H] ⁺ . Example 38 N- (4-cyanobenzyl)-6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (38)

N- (4-Cyanobenzyl)-6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (38) was obtained using the procedure described in Example 3 with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H- pyrazolo[3,4-c]pyridine -pyrazolo[3,4- c ]pyridine-3-carboxylic acid (int-17). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (m, 2H), 7.46 (m, 2H), 7.29 (m, 1H), 6.66-6.34 (m, 1H), 4.66 (m, 2H), 4.16 (s, 3H), 4.01 (s, 2H), 3.76 (m, 2H), 3.21 (t, J = 6.8 Hz, 2H), 1.74-1.66 (m, 2H), 1.36-1.27 (m, 2H). MS (ESI): m / z 478.1 [M+H] ⁺ . Example 39 N- (4-Chlorobenzyl)-6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (39)

N- (4-Chlorobenzyl)-6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (39) was obtained using the procedure described in Example 3 with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((difluoromethyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H- pyrazolo[3,4-c]pyridine -pyrazolo[3,4- c ]pyridine-3-carboxylic acid (int-17) and 4-(aminomethyl)benzonitrile hydrochloride was replaced by (4-chlorophenyl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.28 (m, 4H), 7.18 (m, 1H), 6.64-6.35 (m, 1H), 4.57 (m, 2H), 4.15 (s, 3H), 4.01 (s, 2H), 3.75 (t, J = 6.8 Hz, 2H), 3.22 (t, J = 6.8 Hz, 2H), 1.72-1.66 (m, 2H), 1.34-1.28 (m, 2H). MS (ESI): m / z 487.2 [M+H] ⁺ . Example 40 N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (40)

N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (40) was obtained using the procedure described in Example 28, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl) -1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-20). MS (ESI): m/z 456.3 [M+H] ⁺ Example 41 and Example 42 (R)- or (S)- N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (41) and (R)- or (S)- N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (42)

(R)- or (S)- N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (41) and (R)- or (S)- N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (42) was obtained by SFC separation of N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (40). Unless otherwise indicated, the examples indicate relative stereochemistry.

SFC: Chiralpak AD-3, 5-40% (MeOH+0.05% Et ₂ NH), 3 mL/min

(R)- or (S)- N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (41): Peak 1: SFC R _t = 3.033 min, AD-3S_3_5_40_3ML_T35. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.30 (t, J = 6.4 Hz, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 14.8 Hz, 1H), 4.18 (s, 3H), 4.13-4.08 (m, 1H), 3.45 (d, J = 14.4 Hz, 1H), 3.28-3.25 (m, 2H), 3.00 (s, 3H), 1.57-1.54 (m, 1H), 1.52-1.46 (m, 1H), 1.28-1.25 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.03-0.97 (m, 1H). MS (ESI): m / z 456.3 [M+H] ⁺ .

(R)- or (S)- N-(4-cyanobenzyl)-1,5-dimethyl-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (42): Peak 2: SFC R _t = 4.134 min, AD-3S_3_5_40_3ML_T35. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.8 Hz, 2H), 7.30 (t, J = 6.4 Hz, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.44 (d, J = 14.8 Hz, 1H), 4.18 (s, 3H), 4.13-4.08 (m, 1H), 3.45 (d, J = 14.4 Hz, 1H), 3.28-3.25 (m, 2H), 3.00 (s, 3H), 1.57-1.54 (m, 1H), 1.52-1.46 (m, 1H), 1.28-1.25 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.01-0.97 (m, 1H). MS (ESI): m / z 456.4 [M+H] ⁺ . Example 43 N- (4-Cyanobenzyl)-1-cyclopropyl-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (43)

N- (4-cyanobenzyl)-1-cyclopropyl-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (43) was obtained using the procedure described in Example 1, with the exception that ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-6) was replaced with ethyl 1-cyclopropyl-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-21). TLC R _f = 0.2 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.24-7.21 (m, 1H), 4.64 (d, J = 6.4 Hz, 2H), 4.57-4.52 (m, 1H), 4.09 (s, 2H), 3.75-3.72 (m, 2H), 3.20-3.17 (m, 2H), 2.78-2.74 (m, 1H), 1.53-1.50 (m, 2H), 1.28-1.22 (m, 6H), 1.10-1.03 (m, 6H). MS (ESI): m / z 494.2 [M+H] ⁺ . Example 44 N -(4-Chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (44)

Step 1: N- (4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the procedure described in Example 28, Step 1, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid (int-24) and NH ₄ Cl was replaced with (4-chlorophenyl)methanamine. MS (ESI): m / z 583.0 [M+H] ⁺ .

Step 2: A solution of N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (110 mg, 0.19 mmol, 1.0 equiv) in TFA (2 mL) was stirred at 80 °C for 2 h and then concentrated. The residue was purified by RP-HPLC to give N- (4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (44). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.75 (br s, 1H), 7.41-7.24 (m, 4H), 4.38 (br d, J = 6.1 Hz, 2H), 4.02 (s, 2H), 3.63 (br t, J = 6.7 Hz, 2H), 3.06-2.86 (m, 3H), 1.29-1.22 (m, 2H), 1.11-1.05 (m, 2H), 1.05-0.94 (m, 4H). MS (ESI): m / z 463.2 [M+H] ⁺ . Example 45 N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (45)

N- (4- Cyanobenzyl )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (45) was obtained using the method described for N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (44) with the exception that (4-chlorophenyl)methanamine was replaced by 4-(aminomethyl)benzonitrile hydrochloride. TLC R _f = 0.4 (EtOAc). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.76 (s, 1H), 7.79-7.77 (m, 2H), 7.48 (d, J = 8.4 Hz, 2H), 4.47 (d, J = 6.0 Hz, 2H), 4.01 (s, 2H), 3.60-3.58 (m, 2H), 2.97-2.93 (m, 3H), 1.25-1.24 (m, 2H), 1.06-1.00 (m, 6H). MS (ESI): m / z 454.2 [M+H] ⁺ . Example 46 4-((8-((1-(methylsulfonyl)cyclopropyl)methyl)-1,7-dioxo-3,4,7,8,9,10-hexahydropyrido[3',4':3,4]pyrazolo[1,5- a ]pyrrolidino-2( 1H )-yl)methyl)benzonitrile (46)

Step 1: 6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate was obtained using the PMB protecting group removal method described in Example 44, Step 2, with the exception that N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was replaced with 1-(4-methoxybenzyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-27). TLC R _f = 0.3 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 12.04 (s, 1H), 4.44-4.39 (m, 2H), 4.02 (s, 2H), 3.84-3.81 (m, 2H), 3.18-3.15 (m, 2H), 3.07 (s, 3H), 1.59-1.57 (m, 3H), 1.41 (t, 2H), 1.13-1.10 (m, 2H). MS (ESI): m / z 342.2 [M+H] ⁺ .

Step 2: 6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthesis of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate. TLC R _f = 0.2 (1:10 MeOH/EtOAc). MS (ESI): m / z 313.9 [M+H] ⁺ .

Step 3: 4-((8-((1-(methylsulfonyl)cyclopropyl)methyl)-1,7-dioxo-3,4,7,8,9,10-hexahydropyrido[3',4':3,4]pyrazolo[1,5- a ]pyrrolidone-2(1 H 4-(((2-bromoethyl)amino)methyl)benzonitrile (46) was obtained using the procedure described in Example 28, step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and _NH4Cl was replaced with 4-(((2-bromoethyl)amino)methyl)benzonitrile (int-25). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 4.80 (s, 2H), 4.44-4.41 (m, 2H), 4.03 (s, 2H), 3.81-3.77 (m, 2H), 3.72-3.69 (m, 2H), 3.21-3.18 (m, 2H), 3.08 (s, 3H), 1.55-1.54 (m, 2H), 1.10-1.07 (m, 2H). MS (ESI): m / z 454.4 [M+H] ⁺ . Example 47 N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (47)

Step 1: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate was obtained using the method described for intermediate (int-16) with the exception that 6-methyl-3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one was replaced by 1-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one (see step 1 in the synthesis of intermediate (int-19) and ethyl (Z)-2-chloro-2-(2-methylhydrazono)acetate (int-18) was replaced by ethyl (Z)-2-chloro-2-(2-(4-methoxybenzyl)hydrazono)acetate (int-26). TLC R _f = 0.5 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.27 (d, J = 8.7 Hz, 2H), 6.77-6.72 (m, 2H), 5.68 (s, 2H), 4.33 (q, J = 7.1 Hz, 2H), 4.02-3.94 (m, 1H), 3.99 (s, 1H), 3.69 (s, 3H), 3.66 (t, J = 6.9 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 2.62 (tt, J = 4.9, 8.0 Hz, 1H), 1.47-1.39 (m, 2H), 1.32 (t, J = 7.2 Hz, 3H), 1.19-1.11 (m, 2H), 1.01-0.90 (m, 4H).

Step 2: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate was obtained using the PMB protecting group removal method described in Example 44, Step 2, with the exception that N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was replaced with 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. TLC R _f = 0.3 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.42 (q, J = 7.1 Hz, 2H), 4.13 (s, 2H), 3.83 (t, J = 6.9 Hz, 2H), 3.17 (t, J = 7.0 Hz, 2H), 2.78 (tt, J = 4.9, 8.0 Hz, 1H), 1.57-1.52 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H), 1.26-1.20 (m, 2H), 1.15-1.10 (m, 2H), 1.10-1.06 (m, 2H).

Step 3: To a solution of ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (150 mg, 0.41 mmol, 1.0 equiv), n - _Bu3P (124 mg, 0.62 mmol, 1.5 equiv) and 1,1-bis(hydroxymethyl)cyclopropane (125 mg, 1.23 mmol, 3.0 equiv) in THF (2 mL) was added DIAD (124 mg, 0.62 mmol, 1.5 equiv) at 0°C. The mixture was stirred at 25°C for 6 h, then it was diluted with water (5 mL) and extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was purified by RP-HPLC to give ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl) _-1 -((1-(hydroxymethyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. MS (ESI): m / z 452.0 [M+H] ⁺ .

Step 4: N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (47) was obtained using the procedure described in Example 1 with the exception that ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-6) was replaced with 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 12 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.67 (d, J = 8.0 Hz, 2H), 4.54 (s, 2H), 4.10 (s, 2H), 3.81-3.76 (m, 2H), 3.23 (d, J = 4.0Hz, 3H), 2.92-2.84 (m, 1H), 1.54 (s, 2H), 1.48-1.39 (m, 2H), 1.24 (d, J = 4.0 Hz, 2H), 1.10 (d, J = 4.0 Hz, 2H), 1.05-1.01 (m, 2H), 0.94 (m, 1H), 0.82-0.77 (m, 2H), 0.59-0.53 (m, 2H). MS (ESI): m / z 538.0 [M+H] ⁺ . Example 48 N- (4-cyanobenzyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (48)

N- (4-cyanobenzyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (48) was prepared by using N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-(hydroxymethyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (47) was prepared by the method described above, except that in step 1, 1-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one was replaced by 1-((1-(methylsulfonyl)cyclopropyl)methyl)-3-(N-morpholinyl)-5,6-dihydropyridin-2(1H)-one. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.89-8.86 (m, 1H), 7.80 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 4.60 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 3.97 (s, 2H), 3.69-3.65 (m, 2H), 3.34-3.30 (m, 2H), 3.11 (s, 3H), 3.00-2.97 (m, 2H), 1.29-1.26 (m, 2H), 1.10-1.09 (m, 2H), 0.60-0.57 (m, 2H), 0.42-0.40 (m, 2H). MS (ESI): m / z 512.4 [M+H] ⁺ . Example 49 N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (49)

Step 1: N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 26, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-30) and hydrazine was replaced with 4-(aminomethyl)benzonitrile hydrochloride. TLC _Rf = 0.3 (EtOAc). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.91-8.88 (m, 1H), 7.78-7.75 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H), 6.88-6.85 (m, 2H), 5.65 (s, 2H), 5.32 (br s, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.09 (s, 2H), 3.71 (s, 3H), 3.63-3.59 (m, 4H), 3.00-2.96 (m, 2H), 1.32-1.30 (m, 8H), 0.99-0.96 (m, 2H).

Step 2: N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (49) was obtained using the PMB protecting group removal method described in Step 2 of Example 44, except that N-(4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was replaced with N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.93-8.92 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 5.31 (br s, 1H), 4.48 (d, J = 6.0 Hz, 2H), 4.09 (s, 2H), 3.65-3.60 (m, 4H), 2.99-2.96 (m, 2H), 1.34 (m, 8H), 1.04-0.98 (m, 2H). MS (ESI): m / z 486.3 [M+H] ⁺ . Example 50 N- (4-chlorobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (50)

N- (4-chlorobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4 -c ]pyridine-3-carboxamide (50) was obtained using the method described in Example 26, step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced by 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid (int-32) and hydrazine was replaced by (4-chlorophenyl)methanamine. MS (ESI): m / z 509.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.28 (m, 4H), 7.16 (s, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.17 (s, 2H), 4.14 (s, 3H), 3.86 (br d, J = 5.0 Hz, 2H), 3.71 (t, J = 6.8 Hz, 2H), 3.20 (t, J = 6.9 Hz, 2H), 3.13 (br s, 1H), 1.60 (br s, 2H), 1.51 (s, 6H), 1.27 (s, 1H), 1.11-1.05 (m, 2H).

The compounds given in Table 2 below were prepared according to procedures similar to those described for compound (50) in Example 50 using appropriate amines in place of (4-chlorophenyl)methylamine. Table 2 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 51 N -((6-chloropyridin-3-yl)methyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 510.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.38 (d, J = 2.3 Hz, 1H), 7.68 (dd, J = 2.5, 8.2 Hz, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.22 (s, 1H), 4.59 (d, J = 6.3 Hz, 2H), 4.17 (s, 2H), 4.15 (s, 3H), 3.86 (d, J = 6.3 Hz, 2H), 3.72 (t, J = 6.9 Hz, 2H), 3.18 (t, J = 6.8 Hz, 2H), 3.14-3.05 (m, 1H), 1.62-1.58 (m, 2H), 1.51 (s, 6H), 1.12-1.00 (m, 2H). 52 N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 500.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 7.29 (br s, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.17 (s, 2H), 4.16 (s, 3H), 3.86 (d, J = 5.9 Hz, 2H), 3.72 (t, J = 6.9 Hz, 2H), 3.19 (t, J = 6.9 Hz, 2H), 3.14 (s, 1H), 1.60 (d, J = 2.3 Hz, 2H), 1.51 (s, 6H), 1.12-1.03 (m, 2H). 53 N- (4-Fluorobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 493.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.29 (m, 2H), 7.20-7.10 (m, 1H), 7.07-7.00 (m, 2H), 4.57 (d, J = 6.1 Hz, 2H), 4.17 (s, 2H), 4.14 (s, 3H), 3.86 (s, 2H), 3.71 (t, J = 6.9 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H), 1.62-1.56 (m, 2H), 1.51 (s, 6H), 1.11-1.02 (m, 2H). 54 ( S ) -N- (1-(4-cyanophenyl)ethyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 514.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.74-7.59 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 7.6 Hz, 1H), 5.26 (m, 1H), 4.21-4.11 (m, 5H), 3.86 (d, J = 6.4 Hz, 2H), 3.73-3.65 (m, 2H), 3.17-3.09 (m, 3H), 1.61-1.58 (m, 5H), 1.51 (s, 6H), 1.12-1.00 (m, 2H). SFC: C-07508-092-P2A_1, Rt=1.960, ee=100%, OD-3_5CM_MEOH(DEA)_5_40_3ML_AT35.M 55 ( R ) -N- (1-(4-cyanophenyl)ethyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 514.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (m, 2H), 7.49 (d, J = 7.8 Hz, 2H), 7.11 (m, 1H), 5.26 (m, 1H), 4.17 (s, 5H), 3.86 (s, 2H), 3.69 (m, 2H), 3.14 (m, 3H), 1.59 (d, J = 6.6 Hz, 5H), 1.51 (s, 7H), 1.06 (br s, 2H). SFC: C-07508-092-P1A_1, Rt=1.724, ee=100%, OD-3_5CM_MEOH(DEA)_5_40_3ML_AT35.M Example 56 N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl-1,1 -d ₂ )sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (56)

Step 1: N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (52) (50 mg, 0.100 mmol, 1.0 equiv), NMO (117 mg, 1.001 mmol, 10 equiv) and water (18.03 µl, 1.001 mmol, 10 equiv) were dissolved in MeCN (1 mL), followed by the addition of TPAP (3.52 mg, 10.01 µmol, 0.1 equiv). The solution was stirred at room temperature for 15 minutes, then the reaction mixture was quenched with i -PrOH (5 mL). The solution was diluted with water (1 mL) and acidified to about pH 3 with 1 N _KHSO4 . The aqueous layer was extracted with EtOAc (2 × 25 mL), then the combined organic extracts were dried over _MgSO4 , filtered and concentrated to give 48 mg of crude material. After trituration with diethyl ether, the solid was collected by filtration to give 2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoic acid. MS (ESI): m / z 514.5 [M+H] ⁺ .

Step 2: A mixture of 2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoic acid (40 mg, 0.0785 mmol, 1.0 equiv) and NMM (11.55 μL, 0.105 mmol, 1.34 equiv) in THF (1 mL) was cooled to -5 °C, followed by the addition of isobutyl chloroformate (13.80 μL, 0.105 mmol, 1.34 equiv). After 10 min at -5 °C, the solids were removed by filtration and the filter cake was washed with a small amount of cold THF. The filtrate was cooled to 0 °C and then treated with a solution of NaBD ₄ (6.70 mg, 0.160 mmol, 2.04 equiv) in D ₂ O (26 µL). After 15 min at 0 °C, the reaction mixture was partitioned between EtOAc (10 mL) and water (10 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (3 × 10 mL) and the combined organic extracts were washed with brine (20 mL), dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC to give N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl-1,1- d ₂ )sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (56). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.94 (t, J = 6.3 Hz, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.47 (d, J = 8.3 Hz, 2H), 4.46 (d, J = 6.3 Hz, 2H), 4.09 (d, J = 9.3 Hz, 5H), 3.61 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 1.36-1.29 (m, 8H), 1.02-0.95 (m, 2H). MS (ESI): m / z 502.1 [M+H] ⁺ . Example 57 2-((1-((3-((4-cyanobenzyl)aminomethyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropyl acetate (57)

To a solution of N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (52) (110 mg, 0.22 mmol, 1.0 equiv) in DCM (1 mL) was added acetic anhydride (112 mg, 1.10 mmol, 5.0 equiv) and pyridine (87 mg, 1.10 mmol, 5.0 equiv). The reaction mixture was stirred at 25 °C for 2 h, then it was diluted with water (3 mL) and extracted with EtOAc (3 x 30 mL). After _the combined organic extracts were dried over _Na2SO4 , filtered and concentrated, the residue was purified by RP-HPLC to give 2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropyl acetate (57). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.33-7.29 (m, 1H), 4.66 (d, J = 6.4Hz, 2H), 4.35 (s, 2H), 4.19 (s, 2H), 4.15 (s, 3H), 3.74-3.70 (m, 2H), 3.20-3.16 (m, 2H), 2.20 (s, 3H), 1.60-1.57 (m, 2H), 1.52 (s, 6H), 1.10-1.07 (m, 2H). MS (ESI): m / z 542.2 [M+H] ⁺ . Example 58 N -(4-cyanobenzyl)-6-((1-((1-(difluoromethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (58)

A mixture of N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (52) (50 mg, 0.100 mmol, 1.0 equiv) and CuI (3.81 mg, 0.020 mmol, 0.2 equiv) in MeCN (1.0 _mL ) was heated to 50 °C, followed by the addition of a solution of _FSO2CF2CO2H (26.7 mg, 0.150 mmol, 1.5 equiv) in 300 _µL MeCN dropwise over 10 min. The reaction mixture was heated at 50 °C for an additional 30 min and then concentrated. The residue was diluted with EtOAc (5 mL) and the solids were removed by filtration. The filtrate was concentrated to give a crude oil which was purified by RP-HPLC to give N- (4-cyanobenzyl)-6-((1-((1-(difluoromethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (58). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.96 (t, J = 6.3 Hz, 1H), 7.84 - 7.77 (m, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.80 (t, J = 75.2 Hz, 1H), 4.48 (d, J = 6.3 Hz, 2H), 4.12 (s, 3H), 4.09 (s, 2H), 4.08 (s, 2H), 3.63 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 1.45 (s, 6H), 1.40 - 1.34 (m, 2H), 1.09 - 1.03 (m, 2H). MS (ESI): m/z 550.1 [M+H] ⁺ . Example 59 N- (4-Cyanobenzyl)-6-((1-((2-cyanopropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (59)

Step 1: A suspension of Dess-Martin periodinane (50.8 mg, 0.110 mmol, 1.1 equiv) in _CH2Cl2 ( _2.0 mL) was treated with N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (52) (50 mg, 0.100 mmol, 1.0 equiv). After 2 h at 23 °C, saturated _Na2SO3 (1.0 mL ₎ and saturated _NaHCO3 (1.0 mL) were added, and the biphasic mixture was then stirred for 30 min. The mixture was diluted _{with CH2Cl2} (3 mL), the layers were separated, and _the aqueous layer was then extracted with _CH2Cl2 (2 x 4 mL). The combined organic extracts were dried over _MgSO4 , filtered, and concentrated to give N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.78 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 4.65 (d, J = 6.3 Hz, 2H), 4.14 (s, 3H), 3.96 (s, 2H), 3.67 (t, J = 6.9 Hz, 2H), 3.16 (t, J = 6.9 Hz, 2H), 1.62 (s, 6H), 1.51 - 1.48 (m, 2H), 1.14 - 1.08 (m, 2H). MS (ESI): m/z 498.5 [M+H] ⁺ . Šiška, P., Fodran, P., Szolcsányi, P. Tetrahedron 2014, 70 , 6420-6427.

Step 2: A solution of N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (40 mg, 0.080 mmol, 1.0 equiv) in THF (804 µL) and NH ₄ OH (347 µL) was stirred at 23 °C for 5 min, then I ₂ (61.2 mg, 0.241 mmol, 3.0 equiv) was added and the reaction mixture was heated to 50 °C for 5 h. Saturated _Na2S2O3 (20 mL) was added _and the aqueous layer was extracted _{with CH2Cl2} (3 x 15 mL). _The combined organic extracts were washed with brine, dried over anhydrous _Na2SO4 and concentrated. The residue was purified by column chromatography ( _SiO2 , 40-90% EtOAc/heptane) to give N- (4-cyanobenzyl)-6-((1-(( ₂ -cyanopropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (59). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.63 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 4.66 (d, J = 6.3 Hz, 2H), 4.31 (s, 2H), 4.15 (s, 3H), 3.76 (t, J = 6.8 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H), 1.85 (s, 6H), 1.73 - 1.64 (m, 2H), 1.32 - 1.24 (m, 3H). MS (ESI): m/z 495.5 [M+H] ⁺ . Example 60 N- (4-cyanobenzyl)-6-((1-((1-(3-fluoroaziridocyclobutane-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (60)

A solution of N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (52) (20 mg, 0.04 mmol, 1.0 equiv) and 3-fluoroaziridinecyclobutane (16.4 mg, 0.147 mmol, 3.67 equiv) in DCM (2 mL) was stirred at room temperature for 45 min, followed by the addition of NaBH(OAc) ₃ (200 mg, 0.944 mmol, 23 equiv). After 1 h at room temperature, saturated NaHCO ₃ (2 mL) was added and the biphasic mixture was stirred for 30 min. The organic layer was removed and the aqueous layer was extracted with DCM (2 mL), then the combined organic extracts were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC to give N- (4-cyanobenzyl)-6-((1-((1-(3-fluoroaziridocyclobutan-1-yl)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (60). MS (ESI): m / z 557.3 [M+H] ⁺ .

The compounds given in Table 3 below were prepared according to procedures similar to those described in Examples 56-60. Table 3 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 61 N- (4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-(N-oxolinyl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 569.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.79 (d, J = 8.4 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 4.47 (d, J = 6.4 Hz, 2H), 4.11 (d, J = 6.3 Hz, 5H), 2.98 (t, J = 6.8 Hz, 1H), 2.54 (s, 9H). 62 ( R ) -N- (4-cyanobenzyl)-6-((1-((1-(3-methoxypyrrolidin-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 583.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.97 (t, J = 6.2 Hz, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 6.55 (s, 5H), 4.48 (d, J = 6.3 Hz, 2H), 4.12 (d, J = 9.4 Hz, 5H), 2.99 (t, J = 6.8 Hz, 1H), 1.54 (s, 4H), 1.40 (s, 2H), 1.25 (s, 1H), 1.09 (s, 2H). 63 6-((1-((1-(6-oxa-3-azabicyclo[3.1.1]heptane-3-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 581.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO -d6 ) δ 8.96 (t, J = 6.4 Hz, 1H), 7.86-7.77 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 4.48 (d, J = 6.2 Hz, 2H), 4.42 (s, 1H), 4.18-4.10 (m, 5H), 3.16 (d, J = 11.4 Hz, 1H), 3.06-2.94 (m, 4H), 1.77 (s, 1H), 1.47 (s, 6H), 1.35 (s, 2H), 1.04 (s, 2H). 64 6-((1-((1-(2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 581.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d6 ) δ 8.97 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.1 Hz, 2H), 4.48 (d, J = 6.2 Hz, 2H), 4.13 (s, 5H), 3.64 (s, 6H), 3.00 (s, 1H), 1.77 (s, 2H), 1.37 (m, 6H). 65 N- (4-cyanobenzyl)-6-((1-((1-(3-hydroxyazinocyclobutane-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 555.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d6 ) δ 8.97 (t, J = 6.3 Hz, 1H), 7.86-7.78 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 4.48 (d, J = 6.2 Hz, 4H), 4.13 (s, 3H), 4.09 (s, 2H), 3.64 (t, J = 6.8 Hz, 5H), 3.01 (t, J = 6.7 Hz, 2H), 1.52 (s, 6H), 1.42 (d, J = 7.0 Hz, 2H), 1.14 (s, 2H). 66 N- (4-cyanobenzyl)-6-((1-((1-(3-methoxyazinocyclobutane-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 569.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 7.89 - 7.77 (m, 2H), 7.49 (d, J = 8.3 Hz, 2H), 6.56 (s, 2H), 4.48 (d, J = 6.4 Hz, 8H), 4.13 (s, 11H), 1.51 (s, 3H), 1.41 (s, 1H), 1.13 (s, 1H). 67 N- (4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-(2-oxa-6-azaspiro[3.3]heptane-6-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 581.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d6 ) δ 8.97 (t, J = 6.3 Hz, 1H), 7.86-7.78 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 4.48 (d, J = 6.2 Hz, 2H), 4.22-4.15 (m, 2H), 4.13 (s, 3H), 4.09 (s, 2H), 4.05-3.99 (m, 2H), 3.73 (d, J = 5.0 Hz, 2H), 3.64 (t, J = 6.8 Hz, 4H), 3.00 (t, J = 6.8 Hz, 2H), 1.53 (s, 5H), 1.42 (q, J = 5.1 Hz, 2H), 1.17-1.11 (m, 2H). 68 N- (4-cyanobenzyl)-6-((1-((1-(3-hydroxypyrrolidin-1-yl)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 569.3 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d6 ) δ 8.98 (d, J = 6.5 Hz, 1H), 7.87-7.76 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 6.55 (s, 4H), 4.48 (d, J = 6.3 Hz, 2H), 4.12 (d, J = 10.2 Hz, 5H), 3.81 (s, 2H), 3.64 (s, 4H), 3.00 (d, J = 6.9 Hz, 2H), 1.77 (s, 1H), 1.62 (s, 4H), 1.43 (s, 2H), 1.15 (s, 2H). 69 N- (4-cyanobenzyl)-6-((1-((1-((2-hydroxyethyl)amino)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 543.5 [M+H] ⁺ . ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.63 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 4.65 (d, J = 6.1 Hz, 2H), 4.21 (s, 2H), 4.14 (s, 3H), 3.70 (t, J = 6.8 Hz, 2H), 3.67-3.62 (m, 2H), 3.17 (t, J = 7.2 Hz, 2H), 2.98 (s, 2H), 2.84-2.78 (m, 2H), 1.53 (s, 6H), 1.26 (s, 2H), 1.04 (s, 2H). Example 70 6-((1-((1-amino-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (70)

Step 1: To a solution of N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (52) (500 mg, 1.0 mmol, 1.0 equiv) in DCM (5 mL) was added pyridine (237 mg, 3.0 mmol, 3.0 equiv) and _Tf2O (564 mg, 2.0 mmol, 2.0 equiv) at 0°C. The mixture was stirred at 25°C for 2 h and then concentrated. The residue was purified by column chromatography (SiO ₂ , 25-75% EtOAc/petroleum ether) to give 2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropyl trifluoromethanesulfonate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.30-7.27 (m, 1H), 4.72 (s, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.16 (s, 3H), 4.13 (s, 2H), 3.72-3.69 (m, 2H), 3.21-3.17 (m, 2H), 1.62 (s, 6H), 1.61-1.59 (m, 2H), 1.15-1.12 (m, 2H). MS (ESI): m / z 632.0 [M+H] ⁺ .

Step 2: A mixture of 2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropyl trifluoromethanesulfonate (530 mg, 0.84 mmol, 1.0 equiv) and _NaN3 (300 mg, 4.61 mmol, 5.5 equiv) in DMF (5 mL) was stirred at 80 °C for 2 h. After the mixture was diluted with water (5 mL) and extracted with EtOAc (2 × 30 mL), the combined organic extracts were dried _{over Na2SO4} , filtered and concentrated to give 6-((1-((1-azido-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.30-7.28 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.17 (s, 2H), 4.15 (s, 3H), 3.73-3.70 (m, 4H), 3.20-3.16 (m, 2H), 1.62-1.56 (m, 2H), 1.54 (s, 6H), 1.11-1.08 (m, 2H). MS (ESI): m / z 525.1 [M+H] ⁺ .

Step 3: A mixture of 6-((1-((1-azido-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (300 mg, 0.57 mmol, 1.0 equiv) and 10% Pd/C (30 mg, 0.028 mmol, 0.05 equiv) in EtOAc (12 mL) was placed under H _atmosphere (15 psi), and the mixture was stirred at 25 °C for 30 min. The mixture was filtered and the filtrate was concentrated to give 6-((1-((1-amino-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (70). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.30-7.28 (m, 1H), 4.66 (d, J = 6.0Hz, 2H), 4.19 (s, 2H), 4.16 (s, 3H), 3.74-3.70 (m, 2H), 3.20-3.16 (m, 2H), 3.10 (s, 2H), 1.58-1.57 (m, 2H), 1.50 (s, 6H), 1.07-1.04 (m, 2H). MS (ESI): m / z 499.3 [M+H] ⁺ .

The compounds given in Table 4 below were prepared by direct derivatization of 6-((1-((1-amino-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (70) with an appropriate acylation agent (e.g., see Example 3) or via EDC-mediated amide coupling with an N-Boc amino acid (e.g., see Example 26), followed by removal of the Boc protecting group. Table 4 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 71 N- (4-cyanobenzyl)-6-((1-((1-carboxamido-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 527.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.27 (d, J = 1.6 Hz, 1H), 7.65-7.63 (m, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.30-7.27 (m, 1H), 6.58 (s, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.16 (s, 5H), 3.76 (d, J = 6.0 Hz, 2H), 3.72-3.69 (m, 2H), 3.21-3.17 (m, 2H), 1.58-1.57 (m, 2H), 1.55 (s, 6H), 1.11-1.08 (m, 2H). 72 6-((1-((1-acetamido-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 541.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.30-7.29 (m, 1H), 6.46-6.43 (m, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.16 (s, 5H), 3.72-3.69 (m, 4H), 3.21-3.17 (m, 2H), 2.03 (s, 3H), 1.57-1.56 (m, 2H), 1.53 (s, 6H), 1.11-1.07 (m, 2H). 73 Methyl (2-((1-((3-((4-cyanobenzyl)carbamoyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro- 6H -pyrazolo[3,4- c ]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropyl)carbamate MS (ESI): m / z 557.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 4.67-4.66 (m, 2H), 4.16-4.14 (m, 5H), 3.72-3.70 (m, 2H), 3.69 (s, 3H), 3.64-3.63 (m, 2H), 3.20-3.17 (m, 2H), 1.55-1.53 (m, 2H), 1.53 (s, 6H), 1.09-1.08 (m, 2H). 74 6-((1-((1-(2-aminoacetamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. MS (ESI): m / z 556.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.11 (br s, 1H), 7.95-7.92 (m, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.31-7.28 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.17-4.15 (m, 5H), 3.75-3.69 (m, 4H), 3.43 (s, 2H), 3.20-3.17 (m, 2H), 1.59-1.56 (m, 2H), 1.53 (s, 6H), 1.11-1.08 (m, 2H). 75 ( R )-6-((1-((1-(2-aminopropionamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. MS (ESI): m / z 570.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.05 (s, 1H), 7.95 (s, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.31-7.29 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.17-4.15 (m, 5H), 3.73-3.69 (m, 4H), 3.57-3.53 (m, 1H), 3.20-3.17 (m, 2H), 1.60-1.57 (m, 2H), 1.52 (s, 6H), 1.36 (d, J = 7.2 Hz, 3H), 1.11-1.09 (m, 2H). SFC (C-06637-140-P1B_1, AD-3-IPA(DEA)-40-3mL-35T) Rt=1.155 min, EE value: 100% 76 ( S )-6-((1-((1-(2-aminopropionamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 570.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.07 (s, 1H), 7.94-7.93 (m, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.31-7.29 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.17-4.12 (m, 5H), 3.73-3.69 (m, 4H), 3.58-3.56 (m, 1H), 3.19-3.17 (m, 2H), 1.60-1.57 (m, 2H), 1.52 (s, 6H), 1.37 (d, J = 6.8 Hz, 3H), 1.11-1.08 (m, 2H). SFC (C-06637-141-P1B_1, AD-3-IPA(DEA)-40-3mL-35T) Rt=1.506 min, EE value: 100% 77 6-((1-((1-(2-amino-2-methylpropionamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 584.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.30 (br s, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.29-7.28 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.17-4.15 (m, 5H), 3.73-3.67 (m, 4H), 3.20-3.13 (m, 2H), 1.60-1.57 (m, 2H), 1.51 (s, 6H), 1.37 (s, 6H), 1.11-1.08 (m, 2H). 78 N- (4-cyanobenzyl)-6-((1-((1-(2-(dimethylamino)acetamido)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 584.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.97-8.94 (m, 1H), 7.86-7.83 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.46 (d, J = 6.4 Hz, 2H), 4.11 (s, 3H), 4.07 (s, 2H), 3.63-3.60 (m, 2H), 3.57-3.55 (m 2H), 3.00-2.98 (m, 2H), 2.89 (s, 2H), 2.20 (s, 6H), 1.36 (s, 6H), 1.36-1.34 (m 1H), 1.07-1.04 (m, 2H). Example 79 N-(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (79)

Step 1: A solution of N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (52) (500 mg, 1.0 mmol, 1.0 equiv) in THF (5 mL) was cooled to 0 °C and NaH (60% in mineral oil, 80 mg, 2.0 mmol, 2.0 equiv) was added (gas evolution). The mixture was stirred at 0 °C for 30 min and then ethyl 2-bromo-2-fluoroacetate (370 mg, 2.0 mmol, 2.0 equiv) was added and the mixture was stirred at 60 °C for 4.5 h. The reaction was diluted with _H2O (5 mL) and extracted with EtOAc (3 x 10 mL), then _the combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was purified by RP-HPLC to give ethyl 2-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2-fluoroacetate. TLC _Rf = 0.5 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.33-7.29 (m, 1H), 5.66-5.48 (m, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.35 (q, J = 7.2 Hz, 2H), 4.16 (s, 3H), 4.14-4.11 (m, 2H), 4.01-3.92 (m, 1H), 3.77-3.71 (m, 2H), 3.18 (t, J = 6.8 Hz, 2H), 1.66-1.59 (m, 2H), 1.55 (s, 6H), 1.37 (t, J = 7.2 Hz, 3H), 1.14-1.05 (m, 2H). MS (ESI): m / z 604.3 [M+H] ⁺ .

Step 2: A solution of ethyl 2-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2-fluoroacetate (500 mg, 0.83 mmol, 1.0 equiv) in THF (5 mL) was cooled to -30 °C, then a solution of _NaBH4 (157 mg, 4.14 mmol, 5.0 equiv) in _H2O (5 mL) was added slowly (gas evolution). The resulting mixture was stirred at 20 °C for 1 h, then poured into water (5 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was purified by RP-HPLC to give N- (4-cyanobenzyl ₎ -6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (79). TLC _Rf = 0.3 (EtOAc). MS (ESI): m / z 562.4 [M+H] ⁺ . Example 80 and Example 81 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (80) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (81)

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (80) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (81) was obtained by chiral SFC separation of N- (4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (79).

Unless otherwise indicated, the examples indicate relative stereochemistry.

SFC: CHIRALCEL OJ-3, 5-40% MeOH (0.05% Et ₂ NH), 3 mL/min

Example (80) SFC: Rt = 1.923 min, ee 100%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.30 (m, 1H), 5.49-5.23 (m, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.33-4.23 (m, 2H), 4.15 (s, 3H), 4.12-4.10 (m, 1H), 3.89-3.84 (m, 1H), 3.80 -3.78 (m, 2H), 3.74-3.67 (m, 2H), 3.20-3.17 (m, 2H), 1.57-1.55 (m, 2H), 1.54 (s, 6H), 1.02 (t, J = 5.6 Hz, 2H). MS (ESI): m / z 562.4 [M+H] ⁺ .

Example (81) SFC: Rt = 2.001 min, ee 88 %, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.30 (br s, 1H), 5.47-5.23 (m, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.31-4.23 (m, 2H), 4.15 (s, 3H), 4.12 (d, J = 11.2 Hz, 1H), 3.86 (dd, J = 1.6, 11.2 Hz, 1H), 3.80 (br dd, J = 4.3, 8.7 Hz, 2H), 3.74-3.62 (m, 2H), 3.47 (br s, 1H), 3.19 (t, J = 6.9 Hz, 2H), 1.58 (br d, J = 1.3 Hz, 2H), 1.55 (d, J = 2.4 Hz, 6H), 1.02 (t, J = 5.6 Hz, 2H). MS (ESI): m / z 562.4 [M+H] ⁺ . Example 82 and Example 83 (R)- or (S)- 6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[ 3,4-c]pyridine-3-carboxamide (82) and (R)- or (S)- 6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4 -cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ( 83)

Step 1: A solution of N-(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (79) (550 mg, 0.98 mmol, 1.0 equiv) and _Et3N (0.21 mL, 1.47 mmol, 1.5 equiv) in DCM (10 mL) was cooled to 0 °C, then _Tf2O (0.18 mL, 1.08 mmol, 1.1 equiv) was added dropwise. The resulting mixture was stirred at 20 °C for 1 hour, then the reaction mixture was poured into water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography ( _SiO2 , 50% EtOAc/petroleum ether) to give 2-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2-fluoroethyl trifluoromethanesulfonate. TLC _Rf = 0.3 (50% EtOAc/petroleum ether).

Step 2: A mixture of 2-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2-fluoroethyl trifluoromethanesulfonate (350 mg, 0.50 mmol, 1.0 equiv) and _NaN3 (66 mg, 1.01 mmol, 1.0 equiv) in DMF (5 mL) was stirred at 80 °C for 3 h. The reaction mixture was poured into water (10 mL) and extracted with EtOAc (3 x 15 mL), then the combined organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative TLC (SiO ₂ , EtOAc) to give (6-((1-((1-(2-azido-1-fluoroethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. TLC R _f = 0.5 (EtOAc). MS (ESI): m / z 587.3 [M+H] ⁺ .

Step 3: (6-((1-((1-(2-azido-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (250 mg, 0.43 mmol) was subjected to chiral SFC separation to give (R)- or (S)- 6-((1-((1-(2-azido-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (82-a) and (R)- or (S)- 6-((1-((1-(2-azido-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (82-b). Unless otherwise indicated, the examples indicate relative stereochemistry.

SFC: AmyCoat, 60% EtOH (0.05% Et ₂ NH), 3 mL/min

(82-a): (R)- or (S)- 6-((1-((1-(2-azido-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Chiral SFC peak 1: Rt = 1.100 min, ee 100%. MS (ESI): m / z 587.2 [M+H] ⁺ .

(82-b): (R)- or (S)-6-((1-((1-(2-azido-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide chiral SFC peak 2: Rt = 1.496 min, ee 100%. MS (ESI): m / z 587.3 [M+H] ⁺ .

Step 4a: A mixture of (R)- or (S)-6-((1-((1-(2-azido-1-fluoroethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (82-a) (100 mg, 0.17 mmol) and Pd/C (50 mg) in EtOAc (10 mL) was stirred at 20 °C under hydrogen atmosphere for 2 h, and then the suspension was filtered through a ^Celite® pad. The filter cake was washed with EtOAc (10 mL) and the combined filtrate was concentrated. The residue was purified by RP-HPLC to give (R)- or (S)-6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (82). TLC R _f = 0.3 (1:10 MeOH/EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.21 (br s, 1H), 5.29-5.05 (m, 1H), 4.58 (d, J = 6.4 Hz, 2H), 4.10 (m, 2H), 4.08-4.06 (m, 3H), 4.06-4.01 (m, 1H), 3.80-3.74 (m, 1H), 3.64 (t, J = 6.8 Hz, 2H), 3.16-3.07 (m, 2H), 2.91 (m, 1H), 1.54-1.49 (m, 2H), 1.48-1.41 (m, 6H), 1.02-0.97 (m, 2H). MS (ESI): m / z 561.3 [M+H] ⁺ . SFC R _t = 2.814 min, 100% ee [CHIRALPAK IC-3, 40% EtOH (0.05% Et ₂ NH), 3 mL / min]. Unless otherwise indicated, the examples indicate relative stereochemistry.

Step 4b: (R)- or (S)- 6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (83) is used to obtain (R)- or (S)- 6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c] pyridine-3-carboxamide. ]pyridine-3-carboxamide (82), except that (R)- or (S)-6-((1-((1-(2-azido-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (82-a) is replaced by (R)- or (S)- 6-((1-((1-(2-azido-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (82-b). TLC R _f = 0.3 (1:10 MeOH/EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.56 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.24-7.20 (m, 1H), 5.34-5.13 (m, 1H), 4.58 (d, J = 6.2 Hz, 2H), 4.09 (s, 2H), 4.06 (s, 3H), 4.03 (m, 1H), 3.84-3.75 (m, 1H), 3.67-3.59 (m, 2H), 3.09 (t, J = 6.8 Hz, 2H), 3.01-2.92 (m, 1H), 2.97 (m, 1H), 2.47 (br s, 2H), 1.53-1.48 (m, 2H), 1.46 (d, J = 8.2 Hz, 6H), 1.03-0.94 (m, 2H). MS (ESI): m / z 561.3 [M+H] ⁺ . SFC R _t = 3.214 min, 68% ee [CHIRALPAK IC-3, 40% EtOH (0.05% Et ₂ NH), 3 mL / min]. Unless otherwise indicated, the examples indicate relative stereochemistry. Example 84: N- (4-cyanobenzyl)-6-((1-((1-(1,1-difluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (84)

Step 1: 2-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2,2-difluoroacetic acid was obtained using the method described in Example 79, Step 1, except that ethyl 2-bromo-2-fluoroacetate was replaced with potassium 2-bromo-2,2-difluoroacetate. MS (ESI): m / z 594.2 [M+H] ⁺ .

Step 2: To a mixture of 2-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2,2-difluoroacetic acid (400 mg, 0.67 mmol, 1.0 equiv) in toluene (4 mL) and MeOH (1 mL) at 25 °C was added TMSdiazomethane (2.0 M in hexanes, 1.3 mL, 2.6 mmol, 3.9 equiv). The mixture was stirred at 25 °C for 1 h, then quenched with AcOH (0.2 mL) and concentrated to give methyl 2-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2,2-difluoroacetate. MS (ESI): m / z 608.3 [M+H] ⁺ .

Step 3: N- (4-cyanobenzyl)-6-((1-((1-(1,1-difluoro-2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (84) was obtained using the method described in Example 79, Step 2, except that ethyl 2-(2-((1-((3-((4-cyanobenzyl)aminocarboxyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2-fluoroacetate was replaced with methyl 2-(2-((1-((3-((4-cyanobenzyl)aminocarboxyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2,2-difluoroacetate. A 50 mg portion of the product was purified by RP-HPLC. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.25 (m, 1H), 4.66 (m, 2H), 4.37 (m, 1H), 4.28 (s, 2H), 4.13 (s, 3H), 4.10 (s, 2H), 3.93 (m, 2H), 3.68 (m, 2H), 3.19 (m, 2H), 1.56 (br s, 2H), 1.54 (s, 6H), 1.02-0.95 (m, 2H). MS (ESI): m / z 580.2 [M+H] ⁺ . Example 85 6-((1-((1-(2-amino-1,1-difluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (85)

Step 1: 2-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2,2-difluoroethyl trifluoromethanesulfonate was prepared using the The above method was used to obtain the compound of the present invention, except that N-(4-cyanobenzyl)-6-((1-((1-(1-fluoro-2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (79) was replaced by N- (4-cyanobenzyl)-6-((1-((1-(1,1-difluoro-2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (84). MS (ESI): m / z 712.0 [M+H] ⁺ .

Step 2: 6-((1-((1-(2-azido-1,1-difluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Step 2 of Example 82, except that trifluoromethanesulfonic acid 2-(2-((1-((3-((4-cyanobenzyl)aminocarboxyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2 -methylpropoxy)-2-fluoroethyl trifluoromethanesulfonate was replaced by 2-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)-2,2-difluoroethyl trifluoromethanesulfonate. MS (ESI): m / z 605.1 [M+H] ⁺ .

Step 3: 6-((1-((1-(2-amino-1,1-difluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (85) was obtained using the method described in Example 82, Step 4a, except that ( R )-6-((1-((1-(2-amino-1-fluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c] pyridine-3-carboxamide ]pyridine-3-carboxamide was replaced with 6-((1-((1-(2-azido-1,1-difluoroethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66-7.62 (m, 2H), 7.46 (m, 2H), 7.29 (br s, 1H), 4.66 (d, J = 6.0 Hz, 2H), 4.19-4.10 (m, 7H), 3.71 (m, 2H), 3.21-3.10 (m, 4H), 1.61-1.57 (m, 2H), 1.54 (s, 6H), 1.10-1.04 (m, 2H). MS (ESI): m / z 579.2 [M+H] ⁺ . Example 86 N- (4-cyanobenzyl)-6-((1-((1-(2-hydroxy-2-methylpropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (86)

Step 1: A solution of ethyl 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (see Intermediate (int-32) Synthesis Step 1) (200 mg, 0.48 mmol, 1.0 equiv) in DMF (5 mL) was cooled to 0 °C, followed by the addition of NaH (60% in mineral oil, 39 mg, 0.97 mmol, 2.0 equiv) (gas evolution). The mixture was stirred at 25 °C for 0.5 h, then 2,2-dimethyloxirane (70 mg, 0.97 mmol, 2.0 equiv) was added and the mixture was stirred in a sealed tube at 100 °C for 12 h. The reaction was diluted with _H2O (3 mL) and extracted with EtOAc (3 x 10 mL), then the combined organic extracts were dried _{over Na2SO4} , filtered and concentrated. The residue was purified by RP-HPLC to give 6-((1-((1-(2-hydroxy-2-methylpropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid. MS (ESI): m / z 458.2 [M+H] ⁺ .

Step 2: N- (4-cyanobenzyl)-6-((1-((1-(2-hydroxy-2-methylpropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (86) was obtained using the method described in Example 26, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-(2-hydroxy-2-methylpropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid and hydrazine was replaced with 4-(aminomethyl)benzonitrile hydrochloride. ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.74-7.68 (m, 2H), 7.53 (d, J = 8.4 Hz, 2H), 4.61 (s, 2H), 4.21 (s, 2H), 4.19-4.14 (m, 3H), 3.81-3.70 (m, 4H), 3.38 (s, 2H), 3.10 (t, J = 6.8 Hz, 2H), 1.52 (s, 8H), 1.25 (s, 6H), 1.17-1.09 (m, 2H). MS (ESI): m / z 572.5 [M+H] ⁺ . Example 87 N- (4-cyanobenzyl)-6-((1-((1-(2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (87)

Step 1: To a solution of ethyl 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (see intermediate (int-32) synthesis step 1) (1.5 g, 3.63 mmol, 1.0 equiv) and 3-bromoprop-1-ene (877 mg, 7.26 mmol, 2.0 equiv) in THF (10 mL) was added NaH (60% in mineral oil, 290 mg, 7.26 mmol, 2.0 equiv) at 25 °C (gas evolution). The mixture was stirred at 20 °C for 16 h, then poured into _H2O (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated to give ethyl 6-((1-((1-(allyloxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. MS (ESI): m/z 454.2 [M+H] ⁺ .

Step 2: 6-((1-((1-(2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate was obtained using the method described in step 2 of the synthesis of intermediate (int-29), with the exception that ethyl 1-(4-methoxybenzyl)-6-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate was replaced with ethyl 6-((1-((1-(allyloxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. TLC R _f = 0.4 (EtOAc). MS (ESI): m / z 458.4 [M+H] ⁺ .

Step 3: 6-((1-((1-(2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid was obtained using the method described in the synthesis of intermediate (int-14), with the exception of 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl) 6-((1-((1-(allyloxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13). MS (ESI): m / z 430.2 [M+H] ⁺ .

Step 4: N- (4-cyanobenzyl)-6-((1-((1-(2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (87) was obtained using the method described in Example 26, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced by 6-((1-((1-(2-hydroxyethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid and hydrazine was replaced by 4-(aminomethyl)benzonitrile hydrochloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.31-7.27 (m, 1H), 4.65 (d, J = 6.4 Hz, 2H), 4.26 (s, 2H), 4.14 (s, 3H), 3.87-3.76 (m, 2H), 3.72-3.68 (m, 2H), 3.66 (s, 3H), 3.63-3.59 (m, 2H), 3.43-3.33 (m, 1H), 3.16 (t, J = 6.8 Hz, 2H), 1.56-1.52 (m, 2H), 1.50 (s, 6H), 1.03-0.96 (m, 2H). MS (ESI): m / z 544.3 [M+H] ⁺ . Example 88 N- (4-chlorobenzyl)-6-((1-((1-(2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (88)

Step 1: 6-((1-((1-(allyloxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described in the synthesis of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced with 6-((1-((1-(allyloxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 14.53-11.01 (m, 1H), 5.93 (br s, 1H), 5.32 (br d, J = 16.4 Hz, 1H), 5.19 (br d, J = 8.4 Hz, 1H), 4.08 (br s, 3H), 4.05 (br s, 4H), 3.61 (br s, 4H), 2.95 (br s, 2H), 1.38 (br s, 6H), 1.34 (br s, 2H), 1.00 (br s, 2H). MS (ESI): m / z 426.2 [M+H] ⁺ .

Step 2: 6-((1-((1-(allyloxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 26, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-(allyloxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and hydrazine was replaced with (4-chlorophenyl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.27 (m, 4H), 7.16 (m, 1H), 6.03-5.83 (m, 1H), 5.36-5.29 (m, 1H), 5.24 (m, 1H), 4.57 (d, J = 6.0 Hz, 2H), 4.16 (s, 2H), 4.14 (s, 3H), 4.08-4.03 (m, 2H), 3.73 (m, 2H), 3.63 (s, 2H), 3.17 (m, 2H), 1.65-1.54 (m, 4H), 1.50 (s, 6H), 1.11-1.03 (m, 2H). MS (ESI): m / z 549.2 [M+H] ⁺ .

Step 3. N- (4-chlorobenzyl)-6-((1-((1-(2-hydroxyethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (88) was obtained using the method described in step 2 of the synthesis of intermediate (int-29), with the exception that ethyl 1-(4-methoxybenzyl)-6-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was replaced with 6-((1-((1-(allyloxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.28 (m, 4H), 7.21-7.13 (m, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.27 (s, 2H), 4.22-4.16 (m, 1H), 4.16-4.08 (m, 3H), 3.88-3.78 (m, 2H), 3.74-3.68 (m, 2H), 3.66 (s, 2H), 3.64-3.59 (m, 2H), 3.24-3.14 (m, 2H), 1.60-1.46 (m, 8H), 1.08-0.97 (m, 2H). MS (ESI): m / z 553.3 [M+H] ⁺ . Example 89 N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (89)

Step 1: 6-((1-((1-(allyloxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 26, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-(allyloxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid and hydrazine was replaced with 4-(aminomethyl)benzonitrile hydrochloride. MS (ESI): m / z 540.2 [M+H] ⁺ .

Step 2: A solution of 6-((1-((1-(allyloxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (300 mg, 0.56 mmol, 1.0 equiv) in THF (5 mL) was cooled to 0 °C, followed by the addition of a solution of Hg(OAc) ₂ (354 mg, 1.11 mmol, 2.0 equiv) in _H2O (2 mL). The mixture was stirred at 20 °C for 4 h, followed by the slow addition of a solution of _NaBH4 (53 mg, 1.39 mmol, 2.5 equiv) in _H2O (3 mL). The mixture was stirred at 20 °C for 1 h, then poured into water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative TLC ( _SiO2 , EtOAc) to give N- (4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (89). TLC _Rf = 0.3 (EtOAc). MS (ESI): m / z 558.1 [M+H] ⁺ . Example 90 and Example 91 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (90) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (91)

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (90) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (91) are prepared by N Chiral SFC separation of 1-(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (89) was obtained. Unless otherwise indicated, the examples indicate relative stereochemistry.

SFC: CHIRALPAK IC-3, 40% EtOH (0.05% Et ₂ NH), 3 mL/min.

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (90) SFC: Rt = 4.943 min, ee 100%, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.61 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.30 (br s, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.26 (d, J = 2.0 Hz, 2H), 4.16 (s, 3H), 4.07 (br t, J = 6.2 Hz, 1H), 3.75-3.63 (m, 4H), 3.50 (m, 1H), 3.37 (m, 1H), 3.30 (br s, 1H), 3.18 (t, J = 6.8 Hz, 2H), 1.59-1.55 (m, 2H), 1.53 (d, J = 7.8 Hz, 6H), 1.20 (d, J = 6.4 Hz, 3H), 1.07-0.98 (m, 2H). MS (ESI): m / z 558.4 [M+H] ⁺ .

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxypropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (91). SFC: Rt = 6.035 min. ee 97 %, ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.30 (br s, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.26 (s, 2H), 4.16 (s, 3H), 4.11-4.02 (m, 1H), 3.78-3.62 (m, 4H), 3.54-3.46 (m, 1H), 3.37 (m, 1H), 3.18 (t, J = 6.8 Hz, 2H), 1.59-1.55 (m, 2H), 1.54-1.46 (m, 6H), 1.20 (d, J = 6.54 Hz, 3H), 1.07-0.97 (m, 2H). MS (ESI): m / z 558.4 [M+H] ⁺ . Example 92 6-((1-((1-(2-aminoethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (92)

Step 1: Ethyl 6-((1-((1-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate was obtained using the procedure described in the synthesis of (int-11) with the exception that 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced with tert-butyl 1,2,3-thiazolidine-3-carboxylate 2,2-dioxide. MS (ESI): m / z 457.4 [M-Boc+H] ⁺ .

Step 2: 6-((1-((1-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described in the synthesis of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced with 6-((1-((1-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 429.2 [M-Boc+H] ⁺ .

Step 3: (2-(2-((1-((3-((4-cyanobenzyl)aminomethyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridine-6( 7H tert-butyl)-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.40 (q, J = 7.1 Hz, 2H), 4.30 (s, 2H), 4.21 (s, 3H), 4.18-4.14 (m, 2H), 3.73 (br t, J = 6.8 Hz, 2H), 3.10 (br t, J = 6.7 Hz, 2H), 1.58 (br s, 3H), 1.51 (s, 6H), 1.50 (s, 9H), 1.44-1.34 (m, 4H), 1.14-1.05 (m, 2H). MS (ESI): m / z 543.2 [M-Boc+H] ⁺ .

Step 4: A solution of HCl in MeOH (0.05 mL, 0.187 mmol, 3.0 equiv) was slowly added to a solution of tert-butyl (2-(2-((1-((3-((4-cyanobenzyl)carbamyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)ethyl)carbamate (40 mg, 0.062 mmol, 1.0 equiv) in DCM (2 mL). After 2 h at 25 °C, the reaction mixture was adjusted to pH ₈ with saturated NaHCO3, then the mixture was filtered and purified by RP-HPLC to give 6-((1-((1-(2-aminoethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (92). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.72-7.67 (m, 2H), 7.52 (d, J = 8.4 Hz, 2H), 4.59 (s, 2H), 4.18 (s, 2H), 4.16 (s, 3H), 3.75-3.68 (m, 4H), 3.57 (t, J = 5.4 Hz, 2H), 3.09 (t, J = 6.8 Hz, 2H), 2.88 (t, J = 5.4 Hz, 2H), 1.49-1.48 (m, 2H), 1.53-1.46 (m, 8H), 1.12-1.06 (m, 2H). MS (ESI): m / z 543.4 [M+H] ⁺ .

Compound 5 given in Table 5 below was prepared using a method similar to that described in Example 92. Table 5 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 93 6-((1-((1-(2-aminoethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)- N -(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. MS (ESI): m / z 552.3 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.33-7.25 (m, 4H), 4.47 (s, 2H), 4.15 (s, 2H), 4.12 (s, 3H), 3.72-3.65 (m, 4H), 3.55 (t, J = 5.4 Hz, 2H), 3.06 (t, J = 6.8 Hz, 2H), 2.86 (t, J = 5.4 Hz, 2H), 1.50-1.43 (m, 8H), 1.09-1.03 (m, 2H). 94 6-((1-((1-(2-aminoethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-fluorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide MS (ESI): m / z 536.1 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.38-7.35 (m, 2H), 7.09-7.00 (m, 2H), 4.51 (s, 2H), 4.20 (s, 2H), 4.16 (s, 3H), 3.78-3.69 (m, 4H), 3.67-3.56 (m, 2H), 3.11 (t, J = 6.8 Hz, 2H), 2.94 (t, J = 5.4 Hz, 2H), 1.58-1.44 (m, 8H), 1.15-1.02 (m, 2H). 95 6-((1-((1-((2-aminoethoxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)- N -(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 550.4 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.34 (s, 4H), 4.52 (s, 2H), 4.17 (s, 5H), 3.82 (s, 2H), 3.72 (t, J = 6.8 Hz, 2H), 3.58 (t, J = 5.4Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 2.92 (t, J = 5.4 Hz, 2H), 1.52-1.46 (m, 4H), 1.21-1.16 (m, 2H), 1.14-1.10 (m, 2H), 96 6-((1-((1-((2-aminoethoxy)methyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide MS (ESI): m / z 541.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.97 (t, J = 6.4 Hz, 1H), 7.79 (d, J = 7.4Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.47 (d, J = 6.0Hz, 2H), 4.12 (s, 3H), 4.04 (s, 2H), 3.71 (s, 2H), 3.62 (br t, J = 6.6 Hz, 2H), 3.42 (t, J = 5.8 Hz, 2H), 2.98 (br t, J = 6.8 Hz, 2H), 2.72 (t, J = 5.8 Hz, 2H), 1.32 (br s, 4H), 1.16-1.11 (m, 2H), 1.06-1.01 (m, 2H). 97 (R)- or (S)- 6-((1-((1-(2-aminopropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)- N -(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 566.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.26 (m, 4H), 7.19 (br t, J = 6.2 Hz, 1H), 4.57 (d, J = 6.2 Hz, 2H), 4.18 (s, 2H), 4.14 (s, 3H), 3.80-3.68 (m, 3H), 3.66-3.61 (m, 1H), 3.46-3.37 (m, 1H), 3.28-3.13 (m, 4H), 1.72 (br s, 2H), 1.61-1.56 (m, 2H), 1.53 (s, 3H), 1.51 (s, 3H), 1.11-1.02 (m, 5H). SFC R _t = 1.278 min, 100% ee [CHIRALPAK AS-3, 20% EtOH (0.05% Et ₂ NH), 3 mL/min]. 98 (R)- or (S)- 6-((1-((1-(2-aminopropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)- N -(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 566.5 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.38-7.24 (m, 5H), 7.18 (br t, J = 6.2 Hz, 1H), 4.58 (d, J = 6.2 Hz, 2H), 4.18 (s, 2H), 4.14 (s, 3H), 3.79-3.67 (m, 3H), 3.67-3.58 (m, 1H), 3.47-3.33 (m, 1H), 3.29-3.14 (m, 4H), 1.63 (br s, 2H), 1.60-1.57 (m, 2H), 1.53 (s, 3H), 1.51 (s, 3H), 1.12-1.02 (m, 5H). SFC R _t = 1.523 min, 96% ee [CHIRALPAK AS-3, 20% EtOH (0.05% Et ₂ NH), 3 mL/min]. 99 (R)- or (S)- 6-((1-((1-(2-aminopropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 557.2 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.59 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.50 (s, 2H), 4.08 (s, 2H), 4.06 (s, 3H), 3.70-3.50 (m, 4H), 3.38 (m, 1H), 3.18-3.06 (m, 1H), 2.99 (t, J = 6.8 Hz, 2H), 1.41 (s, 3H), 1.39 (s, 5H), 1.05-0.95 (m, 5H). SFC R _t = 2.874 min, 100% ee [CHIRALPAK AS-3, 10-40% EtOH (0.05% Et ₂ NH), 3 mL/min]. 100 (R)- or (S)- 6-((1-((1-(2-aminopropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 557.3 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.64-7.52 (m, 2H), 7.42 (d, J = 8.4 Hz, 2H), 4.50 (s, 2H), 4.13-4.01 (m, 5H), 3.70-3.53 (m, 4H), 3.38 (m, 1H), 3.16-3.07 (m, 1H), 2.99 (t, J = 6.8 Hz, 2H), 1.41 (s, 3H), 1.41-1.36 (m, 5H), 1.05-0.98 (m, 5H). SFC R _t = 3.054 min, 93% ee [CHIRALPAK AS-3, 10-40% EtOH (0.05% Et ₂ NH), 3 mL/min]. Example 101 N- (4-Cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-(2-(methylamino)ethoxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (101)

Step 1: A mixture of NaH (60% in mineral oil, 91 mg, 2.27 mmol, 3.0 equiv) in DMF (5 mL) was cooled to 0 °C and then 6-((1-((1-(2-((tert-butoxycarbonyl)amino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (400 mg, 0.76 mmol, 1.0 equiv) was added (gas evolution). The mixture was stirred at 0 °C for 1 hour and then at 25 °C for 30 minutes. The solution was cooled to 0 °C and then MeI (0.22 mL, 3.78 mmol, 5.0 equiv) was added. The mixture was stirred at room temperature for 10 h, then it was diluted with _H2O (2 mL) and extracted with EtOAc (3 x 2 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated to give crude 6-((1-((1-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid. MS (ESI): m / z 443.2 [M-Boc+H] ⁺ .

Step 2: (2-(2-((1-((3-((4-cyanobenzyl)aminomethyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridine-6( 7H tert-butyl)-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid. MS (ESI): m / z 557.2 [M-Boc+H] ⁺ .

Step 3: N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-(2-(methylamino)ethoxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (101) was obtained using the method described in Step 4 of Example 92, except that tert-butyl (2-(2-((1-((3-((4-cyanobenzyl)aminocarboxyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)ethyl)carbamate was replaced by 6-((1-((1-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid. ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.70 (d, J = 8.2 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 4.61 (s, 2H), 4.20 (s, 2H), 4.18 (s, 3H), 3.76-3.70 (m, 4H), 3.68 (t, J = 5.2 Hz, 2H), 3.10 (t, J = 6.8 Hz, 2H), 2.94-2.89 (m, 2H), 2.51 (d, J = 1.4 Hz, 3H), 1.51 (s, 8H), 1.13-1.07 (m, 2H). MS (ESI): m / z 557.0 [M+H] ⁺ . Example 102 6-((1-((1-(Azocyclobutane-3-yloxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (102)

Step 1: A mixture of ethyl 6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (100 mg, 0.24 mmol, 1.0 equiv), CsOH·H ₂ O (244 mg, 1.45 mmol, 6.0 equiv) and tert-butyl 3-iodoazolobutane-1-carboxylate (205 mg, 0.73 mmol, 3.0 equiv) in DMSO (1.5 mL) was stirred at 80° C. for 12 h, then washed with saturated NH ₄ Cl (1 The mixture was diluted with 1% paraformaldehyde (2-(4-(4-(4-(4-(4-(4-(4-(4-butyloxycarbonyl)azidocyclobutan-3-yl)oxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid). MS (ESI): m / z 441.2 [M-Boc+H] ⁺ .

Step 2: 3-(2-((1-((3-((4-cyanobenzyl)aminomethyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridine-6( 7H tert-butyl)-((1-((1-(tert-butyloxycarbonyl)-azacyclobutan-3-yl)oxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-(tert-butyloxycarbonyl)-azacyclobutan-3-yl)oxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid). MS (ESI): m / z 555.5 [M-Boc+H] ⁺ .

Step 3: 6-((1-((1-(Azocyclobutane-3-yloxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (102) was obtained using the method described in Step 4 of Example 92, except that tert-butyl (2-(2-((1-((3-((4-cyanobenzyl)aminocarboxyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)ethyl)carbamate was replaced by 3-(2-((1-((3-((4-cyanobenzyl)aminocarboxyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)ethyl)carbamate )-1-(4-(4-(4-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropoxy)azidocyclobutane-1-carboxylic acid tert-butyl ester. ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 8.41 (br s, 1H), 7.56 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.26-7.20 (m, 1H), 4.58 (d, J = 6.4 Hz, 2H), 4.40 (br s, 1H), 4.10 (s, 3H), 4.06 (s, 4H), 3.93 (br s, 3H), 3.62 (br t, J = 6.8 Hz, 3H), 3.53 (s, 2H), 3.10 (br t, J = 6.8 Hz, 2H), 1.49-1.45 (m, 2H), 1.43 (s, 5H), 1.01-0.91 (m, 2H). MS (ESI): m / z 555.2 [M+H] ⁺ . Example 103 6-((1-((1-(2-amino-2-methylpropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (103)

Step 1: A mixture of ethyl 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (1.00 g, 2.42 mmol, 1.0 equiv), _Ag2O (0.84 g, 3.63 mmol, 1.5 equiv) and 3-bromo-2-methylprop-1-ene (1.31 g, 9.67 mmol, 4.0 equiv) in DMF (10 mL) was stirred at 25 °C for 12 h and then diluted with _H2O (10 mL). The aqueous mixture was extracted with EtOAc (3 × 15 mL), and the combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , 1:5 EtOAc/petroleum ether) to give 1-methyl-6-((1-((2-methyl-1-((2-methylallyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. TLC R _f = 0.6 (1:5 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.02-4.90 (m, 2H), 4.41 (m, 2H), 4.27-4.18 (m, 3H), 4.15 (s, 2H), 3.98-3.90 (m, 2H), 3.75 (t, J = 6.8 Hz, 2H), 3.65-3.55 (m, 2H), 3.10 (t, J = 6.8 Hz, 2H), 1.76 (s, 3H), 1.60-1.56 (m, 2H), 1.50 (s, 6H), 1.40 (t, J = 7.2 Hz, 3H), 1.13-1.01 (m, 2H).

Step ₂ : Co( _BF4 ) _2-6H2O (17 mg, 0.051 mmol, 0.06 equiv) and (E) _-potassium 2-((3,5-di-tert-butyl-2-hydroxybenzylidene)amino)-2-methylpropanoate (19 mg, 0.051 mmol, 0.06 equiv) were dissolved in EtOH (5 mL) at 20 °C under N2. After 10 minutes, ethyl 1-methyl-6-((1-((2-methyl-1-((2-methylallyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (400 mg, 0.855 mmol, 1.0 equiv) was added followed by p-toluenesulfonylazide (506 mg, 2.566 mmol, 3.0 equiv) and t -BuOOH (5.5 M in decane, 0.05 mL, 0.257 mmol, 0.3 equiv). After 5 minutes, 1,1,3,3-tetramethyldisiloxane (TMDSO) (345 mg, 2.566 mmol, 3.0 equiv) was added dropwise. The resulting solution was stirred at 20 °C for 6 h, then it was quenched with _H2O (5 mL). Saturated _NaHCO3 (4 mL) and brine (5 mL) were added and the reaction mixture was extracted with EtOAc (3 x 10 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography (SiO ₂ , 0-75% EtOAc/petroleum ether) to give ethyl 6-((1-((1-(2-azido-2-methylpropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. MS (ESI): m / z 511.1 [M+H] ⁺ .

NOTE: Potassium (E)-2-((3,5-di-tert-butyl-2-hydroxybenzylidene)amino)-2-methylpropanoate was obtained using a method similar to that described in Waser, J.; Nambu, H.; Carreira, EM Cobalt-catalyzed hydroazidation of olefins: convenient access to alkyl azides. J. Am. Chem. Soc. 2005, 127 , 8294-8295 and Waser, J.; Gaspar, B.; Nambu, H.; Carreira, EM Hydrazines and azides via the metal-catalyzed hydrohydrazination and hydroazidation of olefins J. Am. Chem. Soc. 2006, 128 , 11693-11712.

Specifically, potassium hydroxide (0.5 M in EtOH, 9.3 mL, 4.6 mmol, 1.1 eq) was added to a suspension of 2-amino-2-methylpropionic acid (0.45 g, 4.4 mmol, 1.1 eq) in ethanol (50 mL) under nitrogen at 23 °C. After 30 min, 3,5-di-tert-butyl-salicylic aldehyde (197) (1.0 g, 4.4 mmol, 1.0 eq) was added and the reaction mixture was stirred at 23 °C for 10 h and the solvent was removed under reduced pressure. The separated solid was further dried under high vacuum for 8 h to give 43, which was used without further purification.

Step 3: 6-((1-((1-(2-azido-2-methylpropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxylic acid was obtained using the method described for the synthesis of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 6-((1-((1-(2-azido-2-methylpropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 483.3 [M+H] ⁺ .

Step 4: 6-((1-((1-(2-azido-2-methylpropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-(2-azido-2-methylpropoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. MS (ESI): m / z 597.2 [M+H] ⁺ .

Step 5: 6-((1-((1-(2-amino-2-methylpropoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (103) was obtained using the method described in Example 70, step 3, except that 6-((1-((1-azido-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was replaced with 6-((1-((1-(2-azido-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c] pyridine-3-carboxamide. ]Pyridine-3-carboxamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.31-7.28 (m, 1H), 4.66 (d, J = 6.2 Hz, 2H), 4.18 (s, 2H), 4.15 (s, 3H), 3.76-3.68 (m, 4H), 3.29 (s, 2H), 3.17 (t, J = 6.8 Hz, 2H), 1.97 (br s, 2H), 1.61-1.55 (m, 2H), 1.53 (s, 6H), 1.17 (s, 6H), 1.08-1.03 (m, 2H). MS (ESI): m / z 571.3 [M+H] ⁺ . Example 104 N -(4-cyanobenzyl)-6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (104)

Step 1: 6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. To a solution of ethyl 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (500 mg, 1.2 mmol, 1.0 equiv) in DMF (10 mL) at 25 °C was added NaH (60% in mineral oil, 60 mg, 1.44 The reaction was diluted with water and washed with EtOAc (3 x 3 mL). The organic washes were saved and the aqueous layer was concentrated. The residue was purified by RP-HPLC to give 6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid. MS (ESI): m / z 457.2 [M+H] ⁺ .

Step 2: 6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbonyl chloride. 6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (110 mg, 0.241 mmol, 1.0 equiv) was dissolved in SOCl ₂ (1.5 The solution in 10 mL) was stirred at 60°C for 14 hours, and then concentrated to obtain crude 6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl chloride. MS (ESI): m / z 471.3 [M+H] ⁺ .

Step 3: A mixture of 6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonyl chloride (200 mg, 0.092 mmol, 1.0 equiv) and 4-(aminomethyl)benzonitrile hydrochloride (47 mg, 0.276 mmol, 3.0 equiv) in DMF (0.5 mL) was stirred at 40 °C for 12 h. The reaction was diluted with water (6 mL) and extracted with EtOAc (3 x 3 mL), and the combined organic extracts were concentrated. The residue was purified by RP-HPLC to give N- (4-cyanobenzyl)-6-((1-((1-(2-(dimethylamino)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (104). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.69 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.59 (s, 1H), 4.61-4.58 (m, 1H), 4.19-4.15 (m, 5H), 3.78-3.64 (m, 7H), 3.35 (s, 2H), 3.25 (s, 1H), 3.09 (m, 2H), 2.68 (m, 2H), 2.34 (s, 6H), 1.54-1.46 (m, 8H), 1.13-1.08 (m, 2H). MS (ESI): m / z 571.5 [M+H] ⁺ . Example 105 4-((4-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl) -1H -1,2,3-triazol-1-yl)methyl)benzonitrile (105)

Step 1: A solution of ethyl 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (1.2 g, 2.90 mmol, 1.0 equiv) and DMAP (709 mg, 5.80 mmol, 2.0 equiv) in DMF (10 mL) was cooled to 0 °C, followed by the dropwise addition of TIPSOTf (1.16 g, 3.77 mmol, 1.3 equiv). After the reaction was stirred at 80 °C for 2 h, the mixture was poured into _H2O (10 mL) and extracted with EtOAc (3 x 20 mL), then the combined organic extracts were dried _{over Na2SO4} , filtered and concentrated. The residue was purified by column chromatography ( _SiO2 , 10-100 % EtOAc/petroleum ether) to give 1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.42 (q, J = 7.2 Hz, 2H), 4.22 (s, 3H), 4.17 (s, 2H), 3.97 (s, 2H), 3.75 (t, J = 6.8 Hz, 2H), 3.11 (t, J = 6.8 Hz, 2H), 1.62-1.57 (m, 3H), 1.52 (s, 7H), 1.41 (t, J = 7.2 Hz, 3H), 1.13-1.02 (m, 21H). MS (ESI): m/z 570.3 [M+H] ⁺ .

Step 2: 1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbaldehyde was obtained using the method described in Step 1 of Example 31, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] ethyl pyridine-3-carboxylate (int-12) was replaced with 1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate. MS (ESI): m/z 526.5 [M+H] ⁺ .

Step 3. 3-Ethynyl-1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-5,6-dihydro- 1H -pyrazolo[3,4- c ]pyridine-7( 4H )-one was obtained using the method described in Example 35, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbaldehyde was replaced with 1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbaldehyde. MS (ESI): m/z 522.3 [M+H] ⁺ .

Step 4: 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-1H - 1,2,3-triazol-1-yl)methyl)benzonitrile was obtained using the method described in Example 35, Step 2, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-ethynyl-1-methyl-5,6-dihydro- 1H -pyrazolo[3,4- c ]pyridine-7(4 H )-one was replaced with 3-ethynyl-1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-5,6-dihydro- 1H -pyrazolo[3,4- c ]pyridin-7( 4H )-one. TLC R _f = 0.4 (50% EtOAc/petroleum ether). MS (ESI): m/z 680.3 [M+H] ⁺ .

Step 5: To a solution of 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile (150 mg, 0.22 mmol, 1.0 equiv) in THF (2 mL) was added _Bu4NF (1.0 M in THF, 0.22 mL, 0.22 mmol, 1.0 equiv). The reaction was stirred at 25 °C for 2 h then poured into _H2O (5 mL) and extracted with EtOAc (2 x 5 mL). The combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was purified by column chromatography ( _SiO2 , 0-50% EtOAc/petroleum ether) to give 4-((4-(6-((1-((1-hydroxy _- 2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl) -1H- 1,2,3-triazol-1-yl)methyl)benzonitrile (105). TLC _Rf = 0.2 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.86 (s, 1H), 7.71-7.64 (m, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.67-5.60 (m, 2H), 4.20 (s, 2H), 4.15 (s, 3H), 3.87 (s, 2H), 3.75 (t, J = 6.8 Hz, 2H), 3.25 (t, J = 6.8 Hz, 2H), 3.21-3.07 (m, 1H), 1.61-1.55 (m, 2H), 1.52 (s, 6H), 1.13-1.07 (m, 2H). MS (ESI): m/z 524.4 [M+H] Example 106 4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (106)

Step 1: (E )-1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carbaldehyde oxime was obtained using the method described in Example 31, Step 2, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbaldehyde was replaced with 1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbaldehyde. MS (ESI): m/z 541.3 [M+H] ⁺ .

Step 2: (Z)-N-Hydroxy-1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboimidyl chloride was obtained using the method described in Step 3 of Example 31, except that ( E )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbaldehyde oxime was replaced by ( E )-1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carbaldehyde oxime. MS (ESI): m/z 575.3 [M+H] ⁺ .

Step 3: 4-(3-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile was obtained using the method described in Step 4 of Example 31, except that ( Z )-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl) -N -hydroxy-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboimidyl chloride was replaced with ( Z )- N -hydroxy-1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboimidyl chloride. MS (ESI): m/z 668.4 [M+H] ⁺ .

Step 4: 4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (106) was obtained using the method described in Step 5 of Example 105, except that 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6 4-(3-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile. MS (ESI): m/z 512.1 [M+H] ⁺ . Example 107 and Example 108 ( R )-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (107) and ( S )-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c] pyridin-3-yl)-4,5-dihydroisoxazol-5- yl) benzonitrile (107) ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (108)

( R )-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (107) and ( S )-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (107) ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (108) was obtained by chiral separation of 4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile.

SFC: CHIRALCEL OJ-3, 60% MeOH (0.05% Et ₂ NH), 3 mL/min

( R )-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (107). SCF: >99% ee, Rt = 1.252; ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.70-7.64 (m, 2H), 7.50 (d, J = 8.2 Hz, 2H), 5.74 (m, 1H), 4.18 (s, 2H), 4.14 (s, 3H), 3.95-3.88 (m, 1H), 3.86 (s, 2H), 3.74 (m, 2H), 3.40 (m, 1H), 3.11 (m, 2H), 1.62-1.56 (m, 3H), 1.51 (s, 6H), 1.10-1.04 (m, 2H). MS (ESI): m/z 512.1 [M+H] ⁺ .

( S )-4-(3-(6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-yl)-4,5-dihydroisoxazol-5-yl)benzonitrile (108). SCF: >99% ee, Rt = 1.777); ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.67 (d, J = 8.2 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 5.74 (m, 1H), 4.18 (s, 2H), 4.14 (s, 3H), 3.95-3.88 (m, 1H), 3.86 (s, 2H), 3.74 (t, J = 6.8 Hz, 2H), 3.40 (m, 1H), 3.10 (t, J = 6.8 Hz, 2H), 1.62-1.57 (m, 3H), 1.51 (s, 6H), 1.11-1.05 (m, 2H). MS (ESI): m/z 512.1 [M+H] ⁺ . Example 109 6-((1-((1-amino-2-methyl-1-oxopropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (109)

Step 1: 2-((1-((3-((4-chlorobenzyl)aminoformyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoic acid tert-butyl ester was obtained using the method described in Example 1, with the exception of 6-((1-(cyclopropylsulfonyl) 6-((1-((1-(tert-butyloxy)-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-6) was replaced by 6-((1-((1-(tert-butyloxy)-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (int-34) and 4-(aminomethyl)benzonitrile hydrochloride was replaced by (4-chlorophenyl)methanamine. TLC R _f = 0.2 (50% EtOAc/petroleum ether). MS (ESI): m / z 579.0 [M+H] ⁺ .

Step 2: A solution of tert-butyl 2-((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoate (250 mg, 0.43 mmol, 1.0 equiv) in 4 M HCl in dioxane (5 mL) was stirred at 60 °C for 12 h. The mixture was concentrated to give crude 2-((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoic acid. TLC R _f = 0.2 (1:10 MeOH/EtOAc). MS (ESI): m / z 523.1 [M+H] ⁺ .

Step 3: A solution of 2-((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoic acid in MeOH (2 mL) was treated with _SOCl2 (0.12 mL, 1.65 mmol, 3.8 equiv) at 25 °C. The mixture was stirred at 70 °C for 6 h, then it was quenched with water (2 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts _were dried over _Na2SO4 , filtered and concentrated. The residue was purified by preparative TLC (SiO ₂ , 50% EtOAc/petroleum ether) to give methyl 2-((1-((3-((4-chlorobenzyl)aminomethyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoate. TLC R _f = 0.5 (50% EtOAc/petroleum ether). MS (ESI): m / z 537.1 [M+H] ⁺ .

Step 4: A solution of methyl 2-((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoate (50 mg, 0.09 mmol, 1.0 equiv) in ₄ M NH in MeOH (5 mL) was stirred in a sealed tube at 80 °C for 12 h and then concentrated. The residue was purified by RP-HPLC to give 6-((1-((1-amino-2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (109). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.28 (m, 4H), 7.18-7.15 (m, 1H), 6.82 (s, 1H), 5.59 (s, 1H), 4.56 (d, J = 14 Hz, 2H), 4.12 (s, 3H), 4.10 (s, 2H), 3.69-3.65 (m, 2H), 3.18-3.15 (m, 2H), 1.72 (s, 6H), 1.58-1.55 (m, 2H), 1.14-1.12 (m, 2H). MS (ESI): m / z 522.0 [M+H] ⁺ . Example 110 N- (4-Chlorobenzyl)-1-methyl-6-((1-((2-methyl-1-(methylamino)-1-oxopropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (110)

N- (4-Chlorobenzyl)-1-methyl-6-((1-((2-methyl-1-(methylamino)-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (110) was obtained using the method described in Example 109 for the synthesis of compound (109), except that _NH3 was replaced by methylamine in step 4. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32-7.28 (m, 4H), 7.18-7.15 (m, 1H), 6.76-6.75 (m, 1H), 4.56 (d, J = 6 Hz, 2H), 4.12 (s, 3H), 4.10 (s, 2H), 3.68-3.65 (m, 2H), 3.18-3.15 (m, 2H), 2.86 (d, J = 4 Hz, 3H), 1.70 (s, 6H), 1.51-1.48 (m, 2H), 1.13-1.10 (m, 2H). MS (ESI): m / z 536.1 [M+H] ⁺ . Example 111 and Example 112 (R)- or (S)- N -(4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (111) and (R)- or (S)- N -(4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c ]pyridine-3-carboxamide H -Pyrazolo[3,4- c ]pyridine-3-carboxamide (112)

Step 1: 1-methyl-6-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] ethyl pyridine-3-carboxylate was obtained using the procedure of intermediate (int-6), with the exception that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced by ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by 1-(bromomethyl)-1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropane (int-28). ¹ H NMR (500 MHz, CDCl ₃ ) δ 6.24 (dd, J = 17.5, 10.7 Hz, 1H), 5.52-5.43 (m, 2H), 4.43 (q, J = 7.1 Hz, 2H), 4.23 (s, 3H), 4.10 (s, 2H), 3.73 (t, J = 6.9 Hz, 2H), 3.12 (t, J = 6.8 Hz, 2H), 1.54 (s, 1H), 1.43 (t, J = 7.1 Hz, 3H), 1.06 (d, J = 2.1 Hz, 2H). MS (ESI): m / z 410.3 [M+H] ⁺ .

Step 2: To a solution of NCS (82 mg, 0.611 mmol, 5.0 equiv) in DCE (2.2 ml) was added pyridine (0.593 µL, 7.33 µmol, 0.06 equiv) followed by acetaldehyde oxime (37 µL, 0.608 mmol, 5.0 equiv). The reaction mixture was stirred at room temperature for 30 min, followed by the addition of ethyl 1-methyl-6-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (50 mg, 0.122 mmol, 1.0 equiv). The temperature was raised to 65 °C, then _Et3N (20.42 µL, 0.147 mmol, 1.2 equiv) was added and the mixture was stirred at 65 °C for 3 h. The reaction was diluted with water (2 mL) and the layers were separated. The aqueous layer was extracted with DCM (2 x 2 mL) and the combined organic extracts were dried over _MgSO4 , filtered and concentrated to give crude 1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.43 (q, J = 7.1 Hz, 1H), 4.30-4.18 (m, 2H), 4.09 (s, 1H), 3.81-3.68 (m, 3H), 3.19-3.05 (m, 2H), 2.80 (s, 2H), 2.29 (s, 2H), 2.02 (s, 1H), 1.67-1.55 (m, 4H), 1.48-1.39 (m, 3H), 1.09-1.00 (m, 1H). MS (ESI): m / z 467.8 [M+H] ⁺ .

Step 3: 1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the procedure of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced with 1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.30-4.08 (m, 3H), 3.83-3.65 (m, 1H), 3.16-3.01 (m, 2H), 2.05 (m, 2H), 1.31-1.16 (m, 6H), 1.12 (s, 2H), 0.88 (m, 2H). MS (ESI): m / z 439.2 [M+H] ⁺ .

Step 4. Racemic product ( N- (4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid.

Step 5: (R)- or (S)- N -(4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (111) and (R)- or (S)- N -(4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H-pyrazolo [3,4-c]pyridine-3-carboxamide -pyrazolo[3,4- c ]pyridine-3-carboxamide (112) was obtained by chiral SFC separation of racemic ( N- (4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. Unless otherwise indicated, the examples indicate relative stereochemistry.

SFC: CHIRALPAK AD, 60% EtOH, 5 mL/min

(R)- or (S)- N -(4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (111). 100% ee. Rt = 3.24 min. MS (ESI): m / z 553.2 [M+H] ⁺ .

(R)- or (S)- N -(4-cyanobenzyl)-1-methyl-6-((1-((2-(3-methyl-4,5-dihydroisoxazol-5-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (112). 83% ee. Rt = 4.09 min. MS (ESI): m/z 553.2 [M+H]+. Example 113 N- (4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (113)

Step 1: A solution of ethyl 1-methyl-6-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (see Example 112) (500 mg, 1.22 mmol, 1.0 equiv) in THF (5.0 mL) was cooled to -10 °C, then _BH3 (1.0 M in THF, 1.83 mL, 1.83 mmol, 1.5 equiv) was added, and the mixture was stirred at 25 °C for 16 h. The solution was recooled to -10 °C, then NaOH solution (3.0 M, 0.40 mL, 1.22 mmol, 1.0 eq) was added dropwise, followed by H ₂ O ₂ (30%, 166 mg, 1.47 mmol, 1.2 eq). The mixture was stirred at 25 °C for 3 h to complete the oxidation. The reaction mixture was purified by RP-HPLC to give ethyl 6-((1-((4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.45-4.39 (m, 2H), 4.22 (s, 3H), 4.19 (s, 2H), 3.88 (m, 2H), 3.73 (m, 2H), 3.12 (m, 2H), 2.19-2.13 (m, 2H), 1.63-1.58 (m, 2H), 1.56 (s, 5H), 1.43-1.39 (m, 4H), 1.10-1.05 (m, 2H). MS (ESI): m / z 428.2 [M+H] ⁺ .

Step 2: 6-((1-((4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxylic acid was obtained using the method described for the synthetic intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 6-((1-((4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 400.2 [M+H] ⁺ .

Step 3: N- (4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (113) was obtained using the procedure described in Example 26, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced by 6-((1-((4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and hydrazine was replaced by 4-(aminomethyl)benzonitrile hydrochloride. TLC R _f = 0.4 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.31-7.27 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.19 (s, 2H), 4.15 (s, 3H), 3.87 (t, J = 6.4 Hz, 2H), 3.72 (t, J = 6.8 Hz, 2H), 3.18 (t, J = 6.8 Hz, 2H), 2.16 (t, J = 6.4 Hz, 2H), 1.62-1.58 (m, 2H), 1.56 (s, 6H), 1.09-1.03 (m, 2H). MS (ESI): m / z 514.2 [M+H] ⁺ . Example 114 N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (114)

Step 1: To a solution of N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (113) (200 mg, 0.389 mmol, 1.0 equiv) in DCM (5.0 mL) at 0 °C was added Dess-Martin periodane (198 mg, 0.467 mmol, 1.2 equiv). The mixture was stirred at 15 °C for 1 hour, then filtered and concentrated to give crude N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-4-oxobutan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. TLC R _f = 0.7 (EtOAc).

Step 2: To a solution of _CeCl3 (216 mg, 0.879 mmol, 3.0 equiv) in THF (5 mL) was added MeMgBr (3.0 M in _Et2O , 0.2 mL, 0.6 mmol, 2.0 equiv) at -78 °C, then the reaction mixture was stirred at -78 °C for 15 min, then a solution of N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-4-oxobutan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (150 mg, 0.293 mmol, 1.0 equiv) in THF (0.2 mL) was added. After the reaction was stirred at -78 °C for 15 min, it was quenched with saturated _NH4Cl (30 mL) and extracted with EtOAc (3 x 30 mL). The combined organic extracts were dried _{over Na2SO4} , filtered and concentrated. The residue was purified by preparative TLC ( _SiO2 , EtOAc) to give N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. TLC _Rf = 0.4 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.19 (d, J = 3.6 Hz, 2H), 4.15 (s, 3H), 3.72 (t, J = 6.8 Hz, 2H), 3.18 (t, J = 6.8 Hz, 2H), 2.12-2.00 (m, 1H), 1.97-1.87 (m, 1H), 1.63 (s, 3H), 1.61-1.58 (m, 2H), 1.57 (s, 3H), 1.30-1.25 (m, 3H), 1.11-1.02 (m, 2H). MS (ESI): m / z 528.1 [M+H] ⁺ . Example 115 and Example 116 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (115) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (116)

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (115) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (116) was obtained by chiral SFC separation of N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.

Unless otherwise indicated, the examples indicate relative stereochemistry. SFC: AmyCoat, 40% EtOH (0.05% _Et2NH ), 3 mL/min

(R)- or (S)- N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (115). Rt=1.584 min, ee value=100%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (br d, J = 8.0 Hz, 2H), 7.46 (br d, J = 7.6 Hz, 2H), 4.66 (br d, J = 6.4 Hz, 2H), 4.24-4.12 (m, 6H), 3.72 (br t, J = 6.8 Hz, 2H), 3.18 (br t, J = 6.8 Hz, 2H), 2.12-2.00 (m, 1H), 1.98-1.88 (m, 1H), 1.63 (s, 3H), 1.59 (m, 2H), 1.57 (s, 3H), 1.27 (br d, J = 6.0 Hz, 4H), 1.09-1.04 (m, 2H). MS (ESI): m / z 528.3 [M+H] ⁺ .

(R)- or (S)- N-(4-cyanobenzyl)-6-((1-((4-hydroxy-2-methylpentane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (116). SFC (C-07330-076-P2A1_2, Amycoat-EtOH(DEA)-40-3mL-35T.1cm) Rt=2.000 min, ee value=100%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (br d, J = 7.8 Hz, 2H), 7.46 (br d, J = 8.0 Hz, 2H), 4.66 (br d, J = 6.0 Hz, 2H), 4.28-4.10 (m, 6H), 3.72 (br t, J = 6.8 Hz, 2H), 3.28-3.15 (br t, J = 6.8 Hz, 2H), 2.06 (m, 1H), 2.00-1.89 (m, 1H), 1.63 (s, 3H), 1.59 (br s, 2H), 1.56 (s, 3H), 1.27 (br d, J = 6.0 Hz, 4H), 1.07 (br s, 2H). MS (ESI): m / z 528.2 [M+H] ⁺ . Example 117 N -(4-cyanobenzyl)-6-((1-((1-(2-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (117)

Step 1: 1-methyl-7-oxo-6-((1-((1-(2-((triisopropylsilyl)oxy)ethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate was obtained using the procedure of intermediate (int-6), except that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced by ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by ((2-(1-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclopropyl)ethoxy)triisopropylsilane (int-35). MS (ESI): m / z 582.5 [M+H] ⁺ .

Step 2: 6-((1-((1-(2-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate was obtained using the method described in Step 5 of Example 105, except that 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile was replaced with 1-methyl-7-oxo-6-((1-((1-(2-((triisopropylsilyl)oxy)ethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H- pyrazolo [3,4-c]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile. -Ethyl pyrazolo[3,4- c ]pyridine-3-carboxylate. MS (ESI): m / z 426.0 [M+H] ⁺ .

Step 3: 6-((1-((1-(2-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthesis intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 6-((1-((1-(2-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 12.93 (br s, 1H), 4.60 (t, J = 5.2 Hz, 1H), 4.11 (s, 3H), 4.03 (s, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.58-3.49 (m, 2H), 2.96 (t, J = 6.8 Hz, 2H), 2.10 (t, J = 7.0 Hz, 2H), 1.30-1.19 (m, 4H), 1.13-1.02 (m, 4H). MS (ESI): m / z 398.2 [M+H] ⁺ .

Step 4: N-(4-cyanobenzyl)-6-((1-((1-(2-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (117) was obtained using the method described in Example 26, step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-(2-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and hydrazine was replaced with 4-(aminomethyl)benzonitrile hydrochloride. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 4.61 (br s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 4.12 (s, 3H), 4.03 (s, 2H), 3.62 (t, J = 6.8 Hz, 2H), 3.54 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.10 (t, J = 6.8 Hz, 2H), 1.30-1.18 (m, 4H), 1.13-1.02 (m, 4H). MS (ESI): m / z 512.4 [M+H] ⁺ . Example 118 N -(4-cyanobenzyl)-6-((1-((2-hydroxy-2-methylpropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (118)

Step 1: 6-((1-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] pyridine-3-carboxylic acid ethyl ester was obtained using the procedure of intermediate (int-6), with the exception that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5) was replaced by 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by ((1-((1-(bromomethyl)cyclopropyl)sulfonyl)-2-methylpropan-2-yl)oxy)(tert-butyl)dimethylsilane (int-36). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.44-4.39 (m, 2H), 4.24 (s, 3H), 3.94 (s, 2H), 3.78 (t, J = 6.8 Hz, 2H), 3.35 (s, 2H), 3.15 (t, J = 6.8 Hz, 2H), 1.52 (s, 8H), 1.41 (t, J = 7.2 Hz, 3H), 1.07 (d, J = 1.8 Hz, 2H), 0.84 (s, 9H), 0.11 (s, 6H). MS (ESI): m / z 528.4 [M+H] ⁺ .

Step 2: 6-((1-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 1, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-6) was replaced with 6-((1-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.63 (d, J = 8.4 Hz, 2H), 7.50-7.41 (m, 1H), 7.45 (d, J = 8.4 Hz, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.16 (s, 3H), 3.95 (s, 2H), 3.76 (t, J = 6.8 Hz, 2H), 3.38 (s, 2H), 3.20 (t, J = 6.8 Hz, 2H), 1.52 (s, 8H), 1.08-1.01 (m, 2H), 0.84 (s, 9H), 0.12 (s, 6H). MS (ESI): m / z 636.4 [M+Na] ⁺ .

Step 3: N- (4-cyanobenzyl)-6-((1-((2-hydroxy-2-methylpropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (118) was obtained using the method described in Step 5 of Example 105, except that 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was used as the catalyst. In the reaction, 6-((1-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxamide was used to replace 6-((1-((2-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.70 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 4.60 (s, 2H), 4.18 (s, 3H), 4.03 (s, 2H), 3.76 (t, J = 6.8 Hz, 2H), 3.58 (s, 1H), 3.13-3.09 (m, 4H), 1.47-1.42 (m, 6H), 1.15-1.12 (m, 2H), 1.05-1.01 (m, 2H). MS (ESI): m / z 500.4 [M+H] ⁺ . Example 119 N- (4-cyanobenzyl)-6-((1-(((1 s ,3 s )-3-hydroxycyclobutyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (119)

Step 1: 1-methyl-7-oxo-6-((1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ] pyridine-3-carboxylic acid ethyl ester was obtained using the procedure of intermediate (int-6), with the exception that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5) was replaced by 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by ((1 s ,3 s )-3-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane (int-37). MS (ESI): m/z 568.4 [M+H] ⁺ .

Step 2: 1-methyl-7-oxo-6-((1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthesis of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 1-methyl-7-oxo-6-((1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.35-4.27 (m, 1H), 4.24 (s, 3H), 3.94 (s, 2H), 3.76 (t, J = 6.8 Hz, 2H), 3.70-3.60 (m, 1H), 3.14 (t, J = 6.8 Hz, 2H), 2.70-2.59 (m, 2H), 2.54-2.42 (m, 2H), 1.54-1.48 (m, 2H), 1.10-1.01 (m, 22H), 1.00-0.97 (m, 3H). MS (ESI): m/z 540.2 [M+H] ⁺ .

Step 3: N- (4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4- c ]pyridine-3-carboxylic acid (int-11) was replaced with 1-methyl-7-oxo-6-((1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. MS (ESI): m/z 654.2 [M+H] ⁺ .

Step 4: N- (4-cyanobenzyl)-6-((1-(((1 s ,3 s )-3-hydroxycyclobutyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (119) was obtained using the method described in Example 105, step 5, except that 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile was replaced by N- (4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.31-7.28 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.34-4.23 (m, 1H), 4.16 (s, 3H), 3.93 (s, 2H), 3.85-3.75 (m, 1H), 3.72 (m, 2H), 3.19 (m, 2H), 2.76 (m, 2H), 2.50-2.39 (m, 2H), 2.26-2.15 (m, 1H), 1.53-1.48 (m, 2H), 1.03-0.97 (m, 2H). MS (ESI): m/z 498.2 [M+H] ⁺ . Example 120 N- (4-cyanobenzyl)-6-((1-(((1 r ,3 r )-3-hydroxycyclobutyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide (120)

Step 1: 1-Methyl-7-oxo-6-((1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester was obtained using the method described in Step 1 of Example 119, except that ((1 s ,3 s )-3-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclopropyl)triisopropylsilane (int-37) was replaced with ((1 r ,3 r )-3-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclobutoxy)triisopropylsilane (int-38). TLC R _f = 0.4 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.54 (br s, 1H), 4.41 ( J = 7.2 Hz, 2H), 4.31-4.18 (m, 3H), 3.84-3.53 (m, 3H), 3.34-3.17 (m, 1H), 3.16-3.03 (m, 1H), 1.68-1.62 (m, 2H), 1.61 (s, 6H), 1.56 (s, 6H), 1.49 (s, 8H), 1.43-1.39 (m, 3H), 1.38 (s, 2H), 1.09 (s, 2H).

Step 2: 1-methyl-7-oxo-6-((1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described in Step 2 of Example 119, except that 1-methyl-7-oxo-6-((1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c In the reaction mixture, 1-methyl-7-oxo-6-((1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester was replaced with 1-methyl-7-oxo-6-((1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. TLC R _f = 0.2 (1:10 MeOH/EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.58 ( J = 6.2 Hz, 1H), 4.24 (s, 3H), 4.10 (t, J = 3.8 Hz, 1H), 3.93 (s, 2H), 3.80 -3.72 (m, 2H), 3.15 (t, J = 6.8 Hz, 2H), 2.84 ( m , 2H), 2.49-2.38 (m, 2H), 1.59-1.50 (m, 2H), 1.16-0.95 (m, 27H).

Step 3: N- (4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Step 3 of Example 119, except that 1-methyl-7-oxo-6-((1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c In the reaction mixture, 1-methyl-7-oxo-6-((1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was replaced with 1-methyl-7-oxo-6-((1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. TLC R _f = 0.4 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 4.66 (d, J = 6.2 Hz, 2H), 4.59 (m, 1H), 4.16 (s, 3H), 4.15-4.06 (m, 1H), 4.05-3.90 (m, 2H), 3.81-3.69 (m, 2H), 3.19 (m, 2H), 2.84 (m, 2H), 2.50-2.38 (m, 2H), 2.36 (s, 4H), 1.55-1.48 (m, 2H), 1.10-0.99 (m, 23H).

Step 4: N- (4-cyanobenzyl)-6-((1-(((1 r ,3 r )-3-hydroxycyclobutyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide (120) was obtained using the method described in Step 3 of Example 119, except that N- (4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(((1 s ,3 s )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c In the reaction mixture, N- (4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide was replaced with N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(((1 r ,3 r )-3-((triisopropylsilyl)oxy)cyclobutyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide. TLC R _f = 0.3 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.31-7.28 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.61 (m, 1H), 4.23 (m, 1H), 4.16 (s, 3H), 3.93 (s, 2H), 3.73 (m, 2H), 3.25-3.14 (m, 2H), 2.94-2.80 (m, 2H), 2.42 (m, 2H), 1.55-1.47 (m, 3H), 1.08-1.01 (m, 2H). MS (ESI): m/z 498.4 [M+H] ⁺ . Example 121 N- (4-Chlorobenzyl)-1-methyl-7-oxo-6-((1-aminosulfonylcyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (121)

Step 1: 6-((1-(Benzylthio)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Ethyl pyridine-3-carboxylate was obtained using the procedure of intermediate (int-6), except that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced by ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by benzyl(1-(bromomethyl)cyclopropyl)sulfane (int-39). TLC R _f = 0.3 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (s, 5H), 4.42 (q, J = 7.2 Hz, 2H), 4.28 (s, 3H), 3.91 (s, 2H), 3.69-3.61 (m, 2H), 3.55 (s, 2H), 3.17-3.08 (m, 2H), 1.42 (t, J = 7.0 Hz, 3H). MS (ESI): m / z 400.3 [M+H] ⁺ .

Step 2: 6-((1-(Benzylthio)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 1, with the exception that ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-6) was replaced with 6-((1-(benzylthio)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] ethyl pyridine-3-carboxylate and 4-(aminomethyl)benzonitrile hydrochloride was replaced by (4-chlorophenyl)methanamine. TLC R _f = 0.25 (1:10 EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.29 (m, 7H), 7.25-7.16 (m, 2H), 4.58 (d, J = 6.2 Hz, 2H), 4.20 (s, 3H), 3.91 (s, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.57-3.54 (m, 2H), 3.19 (t, J = 6.8 Hz, 2H), 0.86 (s, 4H). MS (ESI): m / z 495.3 [M+H] ⁺ .

Step 3: A 2 dram vial was charged with a mixture of 6-((1-(benzylthio)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (300 mg, 0.606 mmol, 1.0 equiv) in DCM (3 mL) cooled to 0 °C. A second 2 dram vial was charged with NCS (404 mg, 3.03 mmol, 5.0 equiv) in DCM (3 mL) followed by the addition of concentrated HCl (368 mg, 3.636 mmol, 6.0 equiv) dropwise over a few minutes. After 5 minutes, the NCS/HCl solution was added dropwise to the first vial at 0 °C. The vial was removed from the bath and stirred at room temperature for 1 hour. The reaction was poured into water (20 mL) and then extracted with DCM (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried _{over Na2SO4} , filtered and concentrated to give crude 1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropane-1-sulfonyl chloride. MS (ESI): m / z 471.0 [M+H] ⁺ .

Step 4: A solution of _NH3 in THF (0.5 M, 20.0 mL, 10.0 mmol, 11.5 equiv) was cooled to -25 °C and 1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropane-1-sulfonyl chloride (410 mg, 0.869 mmol, 1.0 equiv) was added in one portion. The resulting mixture was stirred at 25 °C for 16 h, then the reaction mixture was concentrated and the residue was purified by RP-HPLC to give N-(4-chlorobenzyl)-1-methyl-7-oxo-6-((1-aminosulfonylcyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (121). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85 (t, J = 6.2 Hz, 1H), 7.41-7.27 (m, 4H), 6.95-6.87 (m, 2H), 4.37 (d, J = 6.4 Hz, 2H), 4.10 (s, 3H), 3.93 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 2.97 (t, J = 6.8 Hz, 2H), 1.23-1.14 (m, 2H), 1.04-0.93 (m, 2H). MS (ESI): m / z 452.2 [M+H] ⁺ . Example 122 ( E ) -N- (4-chlorobenzyl)-6-((1-( N -((dimethylamino)methyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (122)

A solution of N-(4-chlorobenzyl)-1-methyl-7-oxo-6-((1-sulfonylaminocyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (121) (80 mg, 0.177 mmol, 1.0 equiv) in DMF-DMA (1 mL) was stirred at 90 °C for 2 h. The mixture was purified by RP-HPLC to give (E)-N-(4-chlorobenzyl)-6-((1-(N-((dimethylamino)methyl)sulfonylamino)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (122). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85 (t, J = 6.2 Hz, 1H), 7.95 (s, 1H), 7.42-7.28 (m, 4H), 4.38 (d, J = 6.2 Hz, 2H), 4.12 (s, 3H), 3.83 (s, 2H), 3.69 (br t, J = 6.8 Hz, 2H), 3.08 (s, 3H), 3.02-2.96 (m, 2H), 2.87 (s, 3H), 1.25-1.16 (m, 2H), 1.05-0.95 (m, 2H). MS (ESI): m / z 507.0 [M+H] ⁺ . Example 123 N- (4-Cyanobenzyl)-1-methyl-6-((1-( N -methylsulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (123)

Step 1: 6-((1-(Benzylthio)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxylic acid was obtained using the method described for the synthetic intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 6-((1-(benzylthio)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 372.0 [M+H] ⁺ .

Step 2: 6-((1-(Benzylthio)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-(benzylthio)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.33 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.34-7.28 (m, 4H), 7.26-7.19 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.20 (s, 3H), 3.90 (s, 2H), 3.62 (t, J = 6.8 Hz, 2H), 3.55 (s, 2H), 3.17 (t, J = 6.8 Hz, 2H), 1.94-1.55 (m, 2H), 1.43-1.25 (m, 2H), 0.86 (s, 4H). MS (ESI): m / z 486.0 [M+H] ⁺ .

Step 3: 1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropane-1-sulfonyl chloride was obtained using the method described in Step 3 of Example 121, except that (6-((1-(benzylthio)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide) was replaced with 6-((1-(benzylthio)cyclopropyl)methyl ) -N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. TLC R _f = 0.4 (50% EtOAc/petroleum ether). MS (ESI): m / z 461.9 [M+H] ⁺ .

Step ₄ : 1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropane-1-sulfonyl chloride (150 mg, 0.32 mmol, 1.0 equiv) was added portionwise to a solution of methylamine (2.0 M in THF, 0.49 mL, 0.98 mmol, 3.0 equiv) and DIEA (126 mg, 0.97 mmol, 3.0 equiv) in DCM (1.5 mL) at 25 °C under N2 and the resulting mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered and concentrated, and the residue was purified by RP-HPLC to give N- (4-cyanobenzyl)-1-methyl-6-((1-( N -methylsulfamoyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (123). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.97 (m, 1H), 7.79 (d, J = 4.0 Hz, 2H), 7.48 (m, 2H), 7.01 (m, 1H), 4.47 (m, 2H), 4.12 (s, 3H), 3.90 (s, 2H), 3.67 (m, 2H), 2.98 (m, 2H), 2.73-2.62 (m, 3H), 1.21-1.13 (m, 2H), 1.07-0.99 (m, 2H). MS (ESI): m / z 457.2 [M+H] ⁺ .

The other compounds in Table 6 below were prepared according to procedures similar to those described for compound (123) in Example 123. For analogs derived from diamine building blocks, the corresponding mono-Boc diamine was used in the sulfonamide formation and the final compounds were revealed by removal of the protecting group with dioxane containing HCl. Table 6 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR, and/or ¹⁹ F NMR 124 N- (4-cyanobenzyl)-1-methyl-6-((1-(N-oxolinylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 513.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (m, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.46 (d, J = 6.4 Hz, 2H), 4.11(s, 3H), 3.91 (s, 2H), 3.63 (m, 6H), 3.28-3.21 (m, 4H), 2.97 (m, 2H), 1.28-1.20 (m, 2H), 1.09-1.01 (m, 2H). 125 N- (4-cyanobenzyl)-6-((1-((4-hydroxypiperidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 527.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.16 (s, 3H), 3.97 (s, 2H), 3.93 (m, 1H), 3.73 (t, J = 6.8 Hz, 2H), 3.70-3.62 (m, 2H), 3.25-3.20 (m, 2H), 3.20-3.16 (m, 2H), 1.98 (m, 2H), 1.72-1.63 (m, 2H), 1.46-1.39 (m, 2H), 1.08-1.01 (m, 2H). 126 ( R ) -N- (4-cyanobenzyl)-6-((1-((3-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 513.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.32-7.27 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.50 (br s, 1H), 4.29 (d, J = 14.8 Hz, 1H), 4.16 (s, 3H), 3.84-3.74 (m, 1H), 3.73-3.59 (m, 2H), 3.59-3.50 (m, 2H), 3.49-3.43 (m, 2H), 3.21 (m, 2H), 2.15-2.01 (m, 2H), 1.56-1.48 (m, 2H), 1.07-0.93 (m, 2H). SFC R _t = 3.671 min, 100% ee, [CHIRALPAK AD-3, 5-40% i -PrOH (0.05% Et ₂ NH), 3 mL/min]. 127 ( S ) -N- (4-cyanobenzyl)-6-((1-((3-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 513.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.32-7.27 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.49 (br s, 1H), 4.29 (d, J = 14.8 Hz, 1H), 4.16 (s, 3H), 3.84-3.75 (m, 1H), 3.73-3.60 (m, 2H), 3.60-3.49 (m, 2H), 3.53-3.41 (m, 2H), 3.25-3.17 (m, 2H), 2.12-2.04 (m, 2H), 1.58-1.48 (m, 2H), 1.06-0.95 (m, 2H). SFC R _t = 3.594 min, 100% ee, [CHIRALPAK AD-3, 5-40% i -PrOH (0.05% Et ₂ NH), 3 mL/min] 128 N- (4-cyanobenzyl)-6-((1-((3-hydroxyazinocyclobutane-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 499.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.33-7.28 (m, 1H), 4.66 (d, J = 6.4Hz, 2H), 4.64-4.54 (m, 1H), 4.16 (s, 3H), 4.15-4.11 (m, 2H), 3.93-3.89 (s, 2H), 3.91 (m, 2H), 3.77 (t, J = 6.8 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H), 2.59 (br d, J = 7.2 Hz, 1H), 1.46-1.35 (m, 2H), 1.17-1.05 (m, 2H). 129 N -(4-cyanobenzyl)-6-((1-( N -cyclopropylaminosulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 483.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.30 (m, 1H), 6.20 (s, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.16 (s, 3H), 3.91 (s, 2H), 3.73 (m, 2H), 3.19 (m 2H), 2.64-2.55 (m, 1H), 1.60 (br s, 2H), 1.00-0.94 (m, 2H), 0.85-0.78 (m, 2H), 0.75-0.69 (m, 2H). 130 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((3-hydroxy-3-methylpyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 527.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (t, J = 6.4 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 4.92 (s, 1H), 4.46 (d, J = 6.4 Hz, 2H), 4.11 (s, 3H), 3.97-3.87 (m, 2H), 3.64 (t, J = 6.8 Hz, 2H), 3.50-3.37 (m, 2H), 3.27-3.12 (m, 2H), 2.97 (t, J = 6.8 Hz, 2H), 1.89-1.75 (m, 2H), 1.29 (s, 3H), 1.22-1.15 (m, 2H), 1.07-0.98 (m, 2H). SFC R _t = 2.398 min, 100% ee, [CHIRALPAK AS-3, 5-40% MeOH (0.05% Et ₂ NH), 3 mL/min]. 131 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((3-hydroxy-3-methylpyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 527.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (t, J = 6.4 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 4.92 (s, 1H), 4.46 (d, J = 6.4 Hz, 2H), 4.11 (s, 3H), 3.96-3.86 (m, 2H), 3.64 (t, J = 6.8 Hz, 2H), 3.52-3.37 (m, 2H), 3.27-3.13 (m, 2H), 2.97 (t, J = 6.8 Hz, 2H), 1.89-1.74 (m, 2H), 1.29 (s, 3H), 1.24-1.16 (m, 2H), 1.07-0.99 (m, 2H). SFC R _t = 2.518 min, 100% ee, [CHIRALPAK AS-3, 5-40% MeOH(0.05% Et ₂ NH), 3 mL/min] 132 N- (4-cyanobenzyl)-1-methyl-6-((1-( N- (oxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 499.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.32-7.29 (m, 1H), 6.80 (d, J = 8.4Hz, 1H), 4.89-4.86 (m, 2H), 4.80-4.76 (m, 2H), 4.74-4.68 (m, 1H), 4.67 (d, J = 6.4 Hz, 2H), 4.20 (s, 3H), 3.84 (s, 2H), 3.74-3.70 (m, 2H), 3.22-3.19 (m, 2H), 1.48-1.45 (m, 2H), 0.93-0.90 (m, 2H). 133 N- (4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(piperidin-1-ylsulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 512.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (m, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.11 (s, 3H), 3.95-3.83 (m, 2H), 3.63 (m, 2H), 3.45 (m, 1H), 3.25 (m, 1H), 3.20-3.09 (m, 3H), 2.97 (t, J = 6.7 Hz, 2H), 2.75-2.69 (m, 3H), 1.27-1.17 (m, 2H), 1.08-0.99 (m, 2H). 134 6-((1-( N -(3-aminopropyl)sulfonamido)cyclopropyl)methyl)- N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 500.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (br s, 1H), 7.78 (br d, J = 8.0Hz, 2H), 7.47 (br d, J = 8.0 Hz, 2H), 4.46 (br d, J = 6.0 Hz, 2H), 4.11 (s, 3H), 3.90 (s, 2H), 3.62 (br s, 2H), 3.06 (m, 2H), 2.98 (br d, J = 6.4 Hz, 2H), 2.61 (m, 2H), 1.63-1.51 (m, 2H), 1.17 (br s, 2H), 1.01 (br s, 2H). 135 6-((1-( N -(2-aminoethyl)sulfonamido)cyclopropyl)methyl)- N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 486.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (m, 2H), 4.46 (d, J = 6.0 Hz, 2H), 4.12 (s, 3H), 3.91 (s, 2H), 3.66 (m, 2H), 3.04 (m, 3H), 2.97 (m, 2H), 2.71-2.67 (m, 1H), 1.17 (br s, 2H), 1.02 (br s, 2H). 136 N- (4-cyanobenzyl)-1-methyl-6-((1-((4-methylpiperidin-1-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 526.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94-8.92 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.8 Hz, 2H), 4.46 (d, J = 5.6 Hz, 2H), 4.11 (s, 3H), 3.89 (s, 2H), 3.68-3.58 (m, 2H), 3.25 (s, 4H), 2.97 (m, 2H), 2.39-2.33 (m, 3H), 2.18 (s, 3H), 1.25-1.17 (m, 2H), 1.04 (s, 2H). 137 N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-( N -(piperidin-4-yl)sulfonamido)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 526.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (t, J = 6.2 Hz, 1H), 7.78 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.14 (br s, 1H), 4.46 (br d, J = 6.0 Hz, 2H), 4.11 (s, 3H), 3.89 (s, 2H), 3.66 (br t, J = 6.8 Hz, 2H), 3.15 (br s, 1H), 2.97 (br t, J = 6.8 Hz, 2H), 2.89 (br d, J = 12.2 Hz, 2H), 2.43 (m, 2H), 1.79 (br d, J = 10.4 Hz, 2H), 1.33 (m, 2H), 1.21-1.13 (m, 2H), 1.04-0.96 (m, 2H). 138 6-((1-((4-aminopiperidin-1-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 526.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (br t, J = 6.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (br d, J = 8.0 Hz, 2H), 4.46 (br d, J = 6.0 Hz, 2H), 4.11 (s, 3H), 3.87 (s, 2H), 3.67-3.61 (m, 2H), 3.61-3.56 (m, 2H), 3.01-2.96 (m, 2H), 2.95-2.89 (m, 2H), 2.78-2.68 (m, 1H), 1.74 (br d, J = 10.4 Hz, 2H), 1.31-1.21 (m, 2H), 1.20 (br s, 2H), 1.02 (br s, 2H). 139 6-((1-(((3 R ,4 R )-3-amino-4-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)- N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 528.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.93 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (br d, J = 8.0 Hz, 2H), 5.17 (br s, 1H), 4.46 (br d, J = 6.0 Hz, 2H), 4.11 (s, 3H), 4.01-3.87 (m, 2H), 3.84 (br s, 1H), 3.65 (m, 2H), 3.57 (m, 1H), 3.48 (m, 1H), 3.20 (br d, J = 2.2 Hz, 1H), 3.17-3.11 (m, 1H), 3.07 (m, 1H), 2.97 (m, 2H), 1.20 (br s, 2H), 1.02 (br s, 2H SFC R _t = 2.434 min, 100% ee, [CHIRALPAK AD-3, 5-40% i -PrOH (0.05% Et ₂ NH), 3 mL/min]. 140 6-((1-(((3 S ,4 S )-3-amino-4-hydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)- N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 528.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.93 (m, 1H), 7.78 (br d, J = 8.0 Hz, 2H), 7.47 (br d, J = 8.0 Hz, 2H), 5.18 (br s, 1H), 4.46 (br d, J = 6.0Hz, 2H), 4.11 (s, 3H), 4.02-3.87 (m, 2H), 3.84 (br s, 1H), 3.64 (m, 2H), 3.57 (m, 1H), 3.48 (m, 1H), 3.20 (br s, 1H), 3.15 (br d, J = 9.2 Hz, 1H), 3.07 (br d, J = 9.2 Hz, 1H), 2.97 (m, 2H), 1.20 (br s, 2H), 1.02 (br s, 2H). SFC R _t = 2.543 min, 95.8% ee, [CHIRALPAK AD-3, 5-40% i -PrOH (0.05% Et ₂ NH), 3 mL/min]. 141 ( R )-6-((1-((3-aminopyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 512.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (t, J = 6.2 Hz, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 4.46 (br d, J = 6.2 Hz, 2H), 4.11 (s, 3H), 3.97-3.85 (m, 2H), 3.64 (m, 2H), 3.51-3.40 (m, 5H), 3.00-2.96 (m, 2H), 2.96-2.92 (m, 1H), 1.96 (m, 1H), 1.62 (m, 1H), 1.26-1.13 (m, 2H), 1.10-0.96 (m, 2H). SFC R _t = 3.778 min, 100% ee, [CHIRALPAK AD-3, 3-40% MeOH (0.05% Et ₂ NH), 3 mL/min]. 142 ( S )-6-((1-((3-aminopyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 512.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (t, J = 6.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 4.46 (br d, J = 6.0 Hz, 2H), 4.11 (s, 3H), 3.98-3.84 (m, 2H), 3.64 (m, 2H), 3.51-3.40 (m, 5H), 3.01-2.96 (m, 1H), 2.96-2.92 (m, 1H), 1.96 (m, 1H), 1.62 (m, 1H), 1.24-1.16 (m, 2H), 1.08-1.00 (m, 2H). SFC R _t = 5.826 min, 100% ee, [CHIRALPAK AD-3, 3-40% MeOH (0.05% Et ₂ NH), 3 mL/min]. 143 N -(4-chlorobenzyl)-6-((1-( N -(2-hydroxyethyl)sulfonamido)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 496.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.84 (m, 1H), 7.39-7.37 (m, 2H), 7.32-7.30 (m, 2H), 7.08 (s, 1H), 4.79 (s, 1H), 4.37 (br d, J = 6.0 Hz, 2H), 4.11 (s, 3H), 3.92 (s, 2H), 3.67 (m, 2H), 3.47 (m, 2H), 3.06 (m, 2H), 2.98 (m, 2H), 1.21-1.14 (m, 2H), 1.07-0.98 (m, 2H). 144 N -(4-chlorobenzyl)-6-((1-( N -(2-hydroxyethyl)- N -methylsulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 510.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.84 (m, 1H), 7.43-7.34 (m, 2H), 7.34-7.25 (m, 2H), 4.80 (m, 1H), 4.37 (d, J = 6.0 Hz, 2H), 4.10 (s, 3H), 3.90 (s, 2H), 3.63 (m, 2H), 3.55 (m, 2H), 3.24 (m, 2H), 2.98 (m, 2H), 2.89 (s, 3H), 1.31-1.15 (m, 2H), 1.07-0.93 (m, 2H). 145 N -(4-cyanobenzyl)-6-((1-( N -(2-hydroxyethyl)sulfonamido)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 487.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.07 (br s, 1H), 4.79 (m, 1H), 4.46 (br d, J = 6.4 Hz, 2H), 4.12 (s, 3H), 3.92 (s, 2H), 3.67 (m, 2H), 3.47 (m, 2H), 3.06 (m, 2H), 2.97 (m, 2H), 1.23-1.13 (m, 2H), 1.07-0.96 (m, 2H). 146 N- (4-cyanobenzyl)-6-((1-( N- (2-hydroxyethyl) -N -methylsulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 501.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.12-8.87 (m, 1H), 7.78 (br d, J = 8.0 Hz, 2H), 7.47 (br d, J = 7.6 Hz, 2H), 5.00-4.74 (m, 1H), 4.46 (br d, J = 5.6 Hz, 2H), 4.11 (br s, 3H), 3.90 (br s, 2H), 3.63 (m, 2H), 3.55 (br d, J = 5.4 Hz, 2H), 3.29-3.20 (m, 2H), 3.04-2.94 (m, 2H), 2.89 (br s, 3H), 1.22 (br s, 2H), 1.02 (br s, 2H). 147 N -(4-cyanobenzyl)-6-((1-( N -(1,3-dihydroxypropane-2-yl)- N -methylsulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 531.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 7.30 (br t, J = 6.2 Hz, 1H), 6.12 (br d, J = 5.4 Hz, 1H), 4.66 (d, J = 6.2 Hz, 2H), 4.17 (s, 3H), 3.99 (s, 2H), 3.81 (br d, J = 3.6 Hz, 2H), 3.73 (m, 2H), 3.66-3.57 (m, 3H), 3.41 (s, 3H), 3.19 (t, J = 7.0 Hz, 2H), 1.55-1.46 (m, 2H), 0.98-0.93 (m, 2H). 148 N -(4-chlorobenzyl)-6-((1-( N -(1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 523.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85 (br s, 1H), 7.34 (br d, J = 14.8 Hz, 4H), 6.56 (br s, 1H), 4.94 (m, 1H), 4.38 (m, 2H), 4.11 (m, 3H), 3.95 (m, 2H), 3.67 (m, 2H), 3.31 (m, 2H), 2.97 (m, 2H), 1.21 (m, 8H), 1.04 (m, 2H). 149 N -(4-cyanobenzyl)-6-((1-( N -(1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 515.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (m, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 6.56 (s, 1H), 4.94 (m, 1H), 4.47 (d, J = 6.4 Hz, 2H), 4.12 (s, 3H), 3.96 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 3.31 (m, 2H), 2.97 (t, J = 6.8 Hz, 2H), 1.24-1.16 (m, 8H), 1.08-1.02 (m, 2H). 150 N- (4-chlorobenzyl)-6-((1-((3-hydroxyazinocyclobutane-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 508.0 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.31 (m, 2H), 7.31-7.28 (m, 2H), 7.23-7.16 (m, 1H), 4.64-4.57 (m, 2H), 4.56 (s, 1H), 4.14 (s, 3H), 4.14-4.08 (m, 2H), 3.95 (s, 2H), 3.91 (m, 2H), 3.76 (m, 2H), 3.21 (m, 2H), 3.00-2.81 (m, 1H), 1.43-1.37 (m, 2H), 1.14-1.07 (m, 2H). 151 N -(4-Chlorobenzyl)-1-methyl-6-((1-( N -methylsulfonylamino)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 465.9 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.84 (m, 1H), 7.39-7.34 (m, 2H), 7.34-7.27 (m, 2H), 6.99 (m, 1H), 4.37 (d, J = 6.2 Hz, 2H), 4.10 (s, 3H), 3.89 (s, 2H), 3.66 (m, 2H), 2.97 (m, 2H), 2.65 (s, 3H), 1.19-1.12 (m, 2H), 1.05-0.96 (m, 2H). 152 N -(4-chlorobenzyl)-6-((1-( N -(2-hydroxy-2-methylpropyl)sulfonamido)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 524.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85 (m, 1H), 7.40-7.34 (m, 2H), 7.34-7.27 (m, 2H), 6.86 (m, 1H), 4.51 (s, 1H), 4.37 (d, J = 6.4 Hz, 2H), 4.11 (s, 3H), 3.92 (s, 2H), 3.67 (m, 2H), 2.98 (m, 2H), 2.91 (d, J = 6.4 Hz, 2H), 1.23-1.15 (m, 2H), 1.13-1.07 (m, 1H), 1.10 (s, 6H), 1.05-0.97 (m, 2H). 153 N -(4-chlorobenzyl)-6-((1-( N -(1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 540.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85 (m, 1H), 7.40-7.27 (m, 4H), 6.37 (s, 1H), 4.79 (s, 2H), 4.37 (m, 2H), 4.11 (s, 3H), 3.98 (s, 2H), 3.67 (m, 2H), 3.44-3.40 (m, 4H), 2.97 (m, 2H), 1.23-1.12 (m, 5H), 1.05 (m, 2H). 253 6-((1-(N-(4-amino-2-methyl-4-oxobutan-2-yl)sulfonamido)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide LCMS (ESI): m/z 542.2 [M+H] ⁺ 254 N-(4-cyanobenzyl)-6-((1-(N-(3-(dimethylamino)-3-oxopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ¹ H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 6.3 Hz, 1H), 7.84 - 7.70 (m, 2H), 7.57 - 7.31 (m, 2H), 7.02 (t, J = 6.0 Hz, 1H), 4.47 (d, J = 6.3 Hz, 2H), 4.12 (s, 2H), 3.91 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 3.22 (q, J = 6.7 Hz, 2H), 2.96 (d, J = 14.1 Hz, 3H), 2.81 (s, 3H), 1.18 (q, J = 4.7, 4.3 Hz, 1H), 1.15 - 0.83 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -75.15. LCMS (ESI): m/z 542.2 [M+H] ⁺ 255 N-(4-cyanobenzyl)-6-((1-(((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ¹ H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 6.3 Hz, 1H), 7.97 - 7.63 (m, 2H), 7.59 - 7.35 (m, 2H), 7.02 (t, J = 6.0 Hz, 1H), 4.47 (d, J = 6.3 Hz, 2H), 4.12 (s, 3H), 3.91 (s, 2H), 3.67 (t, J = 6.8 Hz, 2H), 3.22 (q, J = 6.7 Hz, 2H), 2.96 (d, J = 14.1 Hz, 5H), 2.81 (s, 3H), 1.18 (q, J = 4.7, 4.3 Hz, 2H), 1.10 - 0.80 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -75.15. LCMS (ESI): m/z 529.2 [M+H] ⁺ 256 N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(1-(oxathiophen-3-yl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ¹ H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 6.2 Hz, 1H), 8.00 - 7.72 (m, 2H), 7.46 (dd, J = 19.9, 8.2 Hz, 2H), 6.91 (d, J = 8.1 Hz, 1H), 4.62 - 4.34 (m, 5H), 4.15 - 4.05 (m, 11H), 4.00 (d, J = 6.9 Hz, 2H), 3.78 - 3.62 (m, 2H), 3.48 (d, J = 5.6 Hz, 2H), 2.97 (t, J = 6.8 Hz, 3H), 2.60 (s, 3H), 1.34 - 1.15 (m, 2H), 1.10 - 0.86 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -74.51 (d, J = 16.4 Hz), -75.22. ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.70 - -77.90 (m). LCMS (ESI): m/z 561.2 [M+H] ⁺ 257 N-(4-cyanobenzyl)-6-((1-(N-(1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ¹ H NMR (400 MHz, methanol-d4) δ 8.92 (t, J = 6.3 Hz, 1H), 8.08 (dt, J = 5.6, 1.2 Hz, 1H), 7.78 - 7.67 (m, 3H), 7.62 - 7.50 (m, 3H), 4.62 (d, J = 7.1 Hz, 1H), 4.62 (s, 2H), 4.16 (d, J = 28.4 Hz, 5H), 4.07 - 3.94 (m, 2H), 3.82 (t, J = 6.8 Hz, 2H), 3.41 (tt, J = 8.2, 2.5 Hz, 2H), 3.12 (t, J = 6.8 Hz, 2H), 1.56 - 1.44 (m, 2H), 1.33 - 1.18 (m, 2H), 0.98 - 0.88 (m, 2H). LCMS (ESI): m/z 530.6 [M+H] ⁺ 258 N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyrimidin-2-ylmethyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ¹ H NMR (400 MHz, methanol-d4) δ 8.79 (d, J = 4.9 Hz, 2H), 7.80 - 7.60 (m, 2H), 7.61 - 7.45 (m, 2H), 7.40 (t, J = 5.0 Hz, 1H), 4.59 (d, J = 21.5 Hz, 3H), 4.19 (s, 2H), 4.04 (s, 2H), 3.77 (t, J = 6.9 Hz, 2H), 3.09 (t, J = 6.9 Hz, 2H), 1.30 (q, J = 4.8 Hz, 2H), 1.09 - 0.81 (m, 2H). ¹⁹ F NMR (376 MHz, methanol-d4) δ -77.99. LCMS (ESI): m/z 532.2 [M+H] ⁺ 259 N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(1-(pyrrolidino-2-yl)ethyl)sulfonamido)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ¹ H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 6.3 Hz, 1H), 8.77 (d, J = 1.5 Hz, 1H), 8.63 - 8.54 (m, 2H), 7.91 (d, J = 8.4 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.48 (d, J = 8.1 Hz, 2H), 4.77 - 4.64 (m, 1H), 4.47 (d, J = 6.2 Hz, 2H), 4.12 (s, 3H), 3.95 (d, J = 14.8 Hz, 1H), 3.73 - 3.59 (m, 11H), 2.94 (t, J = 6.8 Hz, 2H), 1.51 (d, J = 6.9 Hz, 3H), 1.27 - 1.16 (m, 1H), 1.10 - 0.97 (m, 2H), 0.80 - 0.70 (m, 1H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -75.09. LCMS (ESI): m/z 549.6 [M+H] ⁺ 260 N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyridin-2-ylmethyl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ¹ H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 6.3 Hz, 1H), 8.73 (d, J = 1.5 Hz, 1H), 8.64 - 8.55 (m, 2H), 7.88 (t, J = 6.2 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.52 - 7.45 (m, 2H), 4.44 (dd, J = 22.9, 6.2 Hz, 4H), 4.12 (s, 4H), 3.65 (t, J = 6.8 Hz, 3H), 2.96 (t, J = 6.8 Hz, 2H), 1.23 - 1.15 (m, 2H), 1.01 - 0.93 (m, 2H). ¹⁹ F NMR (376 MHz, DMSO) δ -32.26, -75.28, -75.29, -75.30, -75.70, -188.83. LCMS (ESI): m/z 535.1 [M+H] ⁺ 261 N-(4-cyanobenzyl)-6-((1-(N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.98 - 8.90 (m, 1H), 7.83 - 7.76 (m, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.14 (s, 0H), 6.21 (s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 4.12 (d, J = 2.6 Hz, 3H), 4.07 - 3.92 (m, 4H), 3.69 (td, J = 6.8, 3.6 Hz, 5H), 3.61 (s, 5H), 2.97 (t, J = 6.8 Hz, 2H), 1.76 (s, 0H), 1.21 (q, J = 4.9, 4.2 Hz, 2H), 1.07 - 0.99 (m, 2H), 0.08 (s, 0H). ¹⁹ F NMR (376 MHz, DMSO-d6) δ -74.59 (d, J = 3.5 Hz), -74.91. LCMS (ESI): m/z 547.2 [M+H] ⁺ Example 154 N- (4-chlorobenzyl)-6-((1-( N- (1,3-dihydroxy-2-methylpropane-2-yl) -N -methylsulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (154)

Step 1: To a solution of 6-((1-(benzylthio)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (450 mg, 1.21 mmol, 1.0 equiv) in MeOH (5 mL) was added _SOCl2 (0.11 mL, 1.45 mmol, 1.2 equiv) dropwise at 25 °C, and the resulting solution was stirred at 80 °C for 1 h. The mixture was concentrated to give methyl 6-((1-(benzylthio)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. TLC R _f = 0.5 (50% EtOAc/petroleum ether). MS (ESI): m / z 386.1 [M+H] ⁺ .

Step 2: 6-((1-(chlorosulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Methyl pyridine-3-carboxylate was obtained using the method described in Example 121, Step 3, except that (6-((1-(benzylthio)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate was replaced with 6-((1-(benzylthio)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester. Used immediately in Step 3. TLC R _f = 0.5 (25% EtOAc/petroleum ether.

Step 3 6-((1-( N- (1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Methyl pyridine-3-carboxylate was obtained using the method described in Example 123, Step 4, except that 1-((3-((4-cyanobenzyl)aminomethyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropane-1-sulfonyl chloride was replaced with 6-((1-(chlorosulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid methyl ester and methylamine was replaced with 2-amino-2-methylpropane-1,3-diol. MS (ESI): m / z 431.1 [M+H] ⁺ .

Step 4: A solution of methyl 6-((1-(N-(1,3-dihydroxy-2-methylpropan-2-yl)sulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (200 mg, 0.38 mmol, 1.0 equiv) and 2,2-dimethoxypropane (198 mg, 1.90 mmol, 5.0 equiv) in THF (2 mL) was treated with p -TsOH· _H2O (11 mg, 0.06 mmol, 0.16 equiv) at 25 °C. The mixture was stirred at 25 °C for 2 hours, then quenched with NaHCO3, filtered and purified by RP-HPLC to give 1-methyl-7-oxo- ₆ -((1-(N-(2,2,5-trimethyl-1,3-dioxan-5-yl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester. TLC _Rf = 0.6 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.26 (s, 3H), 4.07 (s, 2H), 3.94 (s, 3H), 3.91-3.83 (m, 2H), 3.80-3.70 (m, 4H), 3.14 (t, J = 6.8 Hz, 2H), 1.54 (s, 3H), 1.51-1.48 (m, 2H), 1.47 (s, 3H), 1.29 (s, 3H), 1.04-0.99 (m, 2H).

Step 5: To a solution of methyl 1-methyl-7-oxo-6-((1-(N-(2,2,5-trimethyl-1,3-dioxan-5-yl)sulfamoyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (50 mg, 0.11 mmol, 1.0 equiv) in THF (0.5 mL) was added NaH (60% in mineral oil, 21 mg, 0.53 mmol, 4.8 equiv) at 25 °C (gas evolution). The mixture was stirred at 25 °C for 0.5 h, then iodomethane (301 mg, 2.13 mmol, 19.4 equiv) was added, then the mixture was stirred at 60 °C for 12 h. The reaction was quenched with water (1 mL), adjusted to pH 4-5 with 1 M HCl, and then concentrated. The residue was purified by RP-HPLC to give 1-methyl-6-((1-(N-methyl-N-(2,2,5-trimethyl-1,3-dioxane-5-yl)sulfonamido)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid. MS (ESI): m / z 471.1 [M+H] ⁺ .

Step 6: N- (4-chlorobenzyl)-1-methyl-6-((1-( N -methyl- N- (2,2,5-trimethyl-1,3-dioxane-5-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 1-methyl-6-((1-(N-methyl-N-(2,2,5-trimethyl-1,3-dioxan-5-yl)sulfonamide)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid and 4-(aminomethyl)benzonitrile hydrochloride was replaced with (4-chlorophenyl)methanamine. TLC _Rf = 0.6 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.28 (m, 4H), 7.19-7.15 (m, 1H), 4.57 (d, J = 6.2 Hz, 2H), 4.29 (d, J = 12.4 Hz, 2H), 4.17 (s, 2H), 4.14 (s, 3H), 3.75 (t, J = 6.8 Hz, 2H), 3.69 (d, J = 12.4 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H), 2.92 (s, 3H), 1.52-1.49 (m, 2H), 1.44 (d, J = 7.6 Hz, 6H), 1.33 (s, 3H), 1.14-1.07 (m, 2H).

Step 7: To a solution of N-(4-chlorobenzyl)-1-methyl-6-((1-(N-methyl-N-(2,2,5-trimethyl-1,3-dioxan-5-yl)sulfonamido)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (25 mg, 0.038 mmol, 1.0 equiv) in MeOH (0.3 mL) was added p - _TsOH.H2O (15 mg, 0.076 mmol, 2.0 equiv). The mixture was stirred at 25 °C for 2 h, then quenched with _NaHCO3 and purified by RP-HPLC to give N-(4-chlorobenzyl)-6-((1-(N-(1,3-dihydroxy-2-methylpropan-2-yl)-N-methylsulfamoyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (154). TLC _Rf = 0.2 (EtOAc). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.27 (m, 4H), 7.20 (m, 1H), 4.56 (d, J = 6.2 Hz, 2H), 4.14 (s, 3H), 4.04 (s, 2H), 3.84 (m, 4H), 3.72 (m, 2H), 3.26-3.19 (m, 2H), 2.97 (s, 3H), 1.61-1.54 (m, 2H), 1.33 (s, 3H), 1.11-1.04 (m, 2H). MS (ESI): m / z 554.2 [M+H] ⁺ . Example 155 N- (4-cyanobenzyl)-1-methyl-7-oxo-6-((1-( N- (pyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (155)

Step 1: N- (4-Cyanobenzyl)-1-methyl-7-oxo-6-((1-sulfonylcyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (155a) was obtained using the method described in Example 123, Step 4, except that methylamine was replaced by _NH3 . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.98-8.88 (m, 1H), 7.83-7.76 (m, 2H), 7.47 (m, 2H), 6.91 (m, 1H), 4.46 (d, J = 6.2 Hz, 2H), 4.15-4.10 (m, 3H), 3.97-3.89 (m, 2H), 3.71-3.56 (m, 2H), 3.02-2.91 (m, 2H), 1.25-1.12 (m, 2H), 1.05-0.94 (m, 2H). MS (ESI): m / z 443.1 [M+H] ⁺ .

Step 2: To a solution of N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-sulfaminylcyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (1.0 g, 2.26 mmol, 1.0 eq) in DMF (10 mL) were added 2-bromopyridine (393 mg, 2.49 mmol, 1.1 eq), N , N' -dimethylethylenediamine (100 mg, _{1.14 mmol, 0.5 eq), K2CO3 (} 937 mg, 6.78 mmol, 3.0 eq) and _CuF2 (106 mg, 1.04 mmol, 0.46 eq). The mixture was stirred under _N2 and heated at 130 °C for 2 h, then diluted with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried over _Na2SO4 , filtered and concentrated. The residue was purified by RP-HPLC to give N- (4-cyanobenzyl ₎ -1-methyl-7-oxo-6-((1-( N- (pyridin-2-yl)sulfonamido)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (155). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.93 (m, 1H), 8.01 (br d, J = 4.4 Hz, 1H), 7.84-7.75 (m, 2H), 7.75-7.66 (m, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.20 (br d, J = 8.6 Hz, 1H), 6.86 (br s, 1H), 4.46 (d, J = 6.2 Hz, 2H), 4.08 (s, 3H), 3.94 (s, 2H), 3.66 (m, 2H), 2.91 (m, 2H), 1.35-1.25 (m, 2H), 1.02 (m, 2H). MS (ESI): m / z 519.9 [M+H] ⁺ .

The compounds in Table 7 below were prepared according to procedures similar to those described for compound (155) in Example 155. Table 7 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 156 N -(4-cyanobenzyl)-1-methyl-6-((1-( N -(1-methyl- 1H -pyrazol-3-yl)sulfonylamine)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 523.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.01-8.86 (m, 1H), 7.78 (br d, J = 7.6 Hz, 2H), 7.54 (br s, 1H), 7.47 (br d, J = 7.6 Hz, 2H), 5.98 (br s, 1H), 4.46 (br d, J = 5.76Hz, 2H), 4.11 (s, 3H), 3.95 (br s, 2H), 3.71 (s, 3H), 3.66 (m, 2H), 2.95 (m, 2H), 1.14 (br s, 2H), 0.97 (br s, 2H). 157 N -(4-cyanobenzyl)-1-methyl-6-((1-( N -(6-methylpyridin-2-yl)sulfonamido)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 534.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.92 (m, 1H), 7.90-7.74 (m, 2H), 7.59 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.20-6.99 (m, 1H), 6.83-6.49 (m, 1H), 4.46 (d, J = 6.2 Hz, 2H), 4.08 (s, 3H), 3.94 (s, 2H), 3.66 (m, 2H), 2.90 (m, 2H), 2.29 (s, 3H), 1.29 (br s, 2H), 1.09-0.93 (m, 2H). 158 N -(4-Chlorobenzyl)-1-methyl-7-oxo-6-((1-( N -(pyridin-2-yl)sulfonamido)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 529.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.82 (m, 1H), 8.11-7.93 (m, 1H), 7.74-7.67 (m, 1H), 7.40-7.34 (m, 2H), 7.34-7.28 (m, 2H), 7.20 (br d, J = 8.4 Hz, 1H), 6.93-6.81 (m, 1H), 4.37 (d, J = 6.2 Hz, 2H), 4.07 (s, 3H), 3.94 (s, 2H), 3.66 (m, 2H), 2.91 (m, 2H), 1.30 (m, 2H), 1.07-0.95 (m, 2H). 159 N -(4-cyanobenzyl)-6-((1-( N -(3-methoxypyridin-2-yl)sulfonamido)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 550.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 9.29 (br s, 1H), 8.93 (m, 1H), 7.85-7.75 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.28 (br s, 1H), 7.15-6.49 (m, 1H), 4.46 (d, J = 6.2 Hz, 2H), 4.08 (br s, 3H), 3.99 (br s, 2H), 3.74 (br s, 3H), 3.67 (br s, 2H), 2.85 (br s, 2H), 1.46 (m, 2H), 1.10 (m, 2H). 160 N -(4-cyanobenzyl)-6-((1-( N -(3-methoxy-6-methylpyridin-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 564.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.91 (m, 1H), 7.85-7.75 (m, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.20-7.06 (m, 1H), 6.87-6.68 (m, 1H), 4.46 (d, J = 6.0Hz, 2H), 4.17-4.05 (m, 3H), 3.99 (s, 2H), 3.71 (s, 3H), 3.66 (m, 2H), 2.82 (m, 2H), 2.30 (s, 3H), 1.50 (m, 2H), 1.16-1.05 (m, 2H). 161 N -(4-cyanobenzyl)-1-methyl-6-((1-( N -(2-methylpyridin-3-yl)sulfonamido)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 534.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (m, 1H), 8.22 (m, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.4Hz, 2H), 7.18 (m, 1H), 4.46 (d, J = 6.2 Hz, 2H), 4.11 (s, 3H), 3.97 (s, 2H), 3.67 (m, 2H), 2.95 (m, 2H), 2.54 (br s, 3H), 1.11-1.05 (m, 2H), 1.04-0.96 (m, 2H). 162 N -(4-cyanobenzyl)-6-((1-( N -(2-methoxypyridin-3-yl)sulfonamido)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 550.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (m, 1H), 7.96 (br d, J = 3.6 Hz, 1H), 7.83-7.76 (m, 2H), 7.65 (m, 1H), 7.48 (d, J = 8.4 Hz, 2H), 6.96 (m, 1H), 4.47 (d, J = 6.2 Hz, 2H), 4.12 (s, 3H), 4.01 (s, 2H), 3.92 (s, 3H), 3.68 (m, 2H), 2.95 (m, 2H), 1.06-0.99 (m, 2H), 0.97 (br d, J = 4.4 Hz, 2H). 163 N -(4-cyanobenzyl)-6-((1-( N -(6-methoxypyridin-2-yl)sulfonamido)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 550.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 10.23 (br s, 1H), 8.92 (m, 1H), 7.85-7.73 (m, 2H), 7.57 (m, 1H), 7.47 (d, J = 8.4 Hz, 2H), 6.64 (d, J = 7.6 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 4.46 (d, J = 6.2 Hz, 2H), 4.10 (s, 3H), 3.96 (s, 2H), 3.79 (s, 3H), 3.64 (m, 2H), 2.90 (m, 2H), 1.46-1.35 (m, 2H), 1.15-1.05 (m, 2H). 164 N -(4-cyanobenzyl)-1-methyl-6-((1-( N -(3-methylpyridin-2-yl)sulfonamido)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 534.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.90 (m, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.76-7.67 (m, 1H), 7.59 (br d, J = 6.6 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 6.69 (m, 1H), 4.46 (d, J = 6.2 Hz, 2H), 4.05 (s, 3H), 3.96 (s, 2H), 3.71 (m, 2H), 2.94 (m, 2H), 2.17-2.01 (m, 3H), 1.27 (m, 2H), 0.98 (m, 2H). Example 165 N- (4-Cyanobenzyl)-1-methyl-6-((1-( N- (5-methylisoxazol-3-yl)sulfonamido)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (165)

A solution of 5-methylisoxazol-3-amine (54 mg, 0.55 mmol, 5.0 equiv) in THF (1.0 mL) was cooled to 0 °C, then LiHMDS (1.0 M in THF, 0.55 mL, 0.55 mmol, 5.0 equiv) was added dropwise. The reaction mixture was stirred at 25 °C for 30 min, then 1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropane-1-sulfonyl chloride (90 mg, 0.11 mmol, 55.21% pure, 1.0 equiv) was added. The resulting mixture was stirred at 25 °C for 1.5 hours and then concentrated in vacuo. The residue was purified by RP-HPLC to give N-(4-cyanobenzyl)-1-methyl-6-((1-(N-(5-methylisoxazol-3-yl)sulfonamido)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (165). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (m, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.2 Hz, 2H), 6.08 (s, 1H), 4.46 (d, J = 6.4 Hz, 2H), 4.10 (s, 3H), 3.89 (s, 2H), 3.67 (m, 2H), 2.95 (m, 2H), 2.28 (s, 3H), 1.28-1.20 (m, 2H), 1.01 (m, 2H). MS (ESI): m / z 524.0 [M+H] ⁺ .

The compounds in Table 8 below were prepared according to procedures similar to those described for compound (165) in Example 165. Table 8 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 166 N -(4-Chlorobenzyl)-1-methyl-6-((1-( N -(5-methylisoxazol-3-yl)sulfonamido)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 533.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.84 (br s, 1H), 7.43-7.34 (m, 2H), 7.34-7.20 (m, 2H), 6.06 (s, 1H), 4.37 (br d, J = 5.6 Hz, 2H), 4.09 (s, 3H), 3.88 (br s, 2H), 3.68 (m, 2H), 2.95 (m, 2H), 2.26 (s, 3H), 1.22 (m, 2H), 0.97 (m, 2H). 167 N -(4-cyanobenzyl)-6-((1-( N -(5-cyclopropylisoxazol-3-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 550.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.92 (m, 1H), 7.78 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.0 Hz, 2H), 5.89 (s, 1H), 4.46 (br d, J = 6.4 Hz, 2H), 4.09 (s, 3H), 3.82 (s, 2H), 3.73 (m, 2H), 2.94 (m, 2H), 1.96-1.85 (m, 1H), 1.10 (m, 2H), 0.96-0.87 (m, 2H), 0.86-0.77 (m, 2H), 0.76-0.67 (m, 2H). Example 168 N- (4-Cyanobenzyl)-1-methyl-6-((1-(oxacyclobutane-3-ylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (168)

Step 1: To a solution _{of Na2SO3} (180 mg, 1.43 mmol, 1.0 equiv) in water (2 mL) was added _NaHCO3 (240 mg, 2.86 mmol, 2.0 equiv). The resulting mixture was stirred at 50 °C for 1 hour, followed by the addition of 1-((3-((4-cyanobenzyl)carbamoyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropane-1-sulfonyl chloride (660 mg, 1.43 mmol, 1.0 equiv). The resulting dark mixture was stirred at 50 °C for 12 hours, followed by concentration. The residue was diluted with MeOH (20 mL), the solids were removed by filtration, and the filter cake was washed with MeOH (3 × 20 mL). The filtrate was concentrated and suspended in THF (20 mL). The solids were removed by filtration and the filter cake was washed with THF (3 × 20 mL), followed by concentration of the filtrate to give sodium 1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropane-1-sulfinate. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.92-8.88 (m, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 7.31-7.18 (m, 1H), 4.47 (br d, J = 6.4 Hz, 2H), 4.11 (s, 3H), 3.79-3.74 (m, 2H), 2.93-2.89 (m, 2H), 0.66-0.56 (m, 2H), 0.32 (d, J = 2.4 Hz, 2H).

Step 2: A mixture of sodium 1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropane-1-sulfinate (50 mg, 0.11 mmol, 1.0 equiv) and 3-bromocyclobutane (23 mg, 0.17 mmol, 1.55 equiv) in DMF (1 mL) was stirred at 100 °C for 12 h. The reaction mixture was concentrated and the residue was purified by RP-HPLC to give N-(4-cyanobenzyl)-1-methyl-6-((1-(oxacyclobutan-3-ylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (168). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.71 (d, J = 8.4Hz, 2H), 7.55-7.52 (m, 2H), 5.29-5.18 (m, 1H), 4.95 (d, J = 7.2Hz, 4H), 4.62 (s, 2H), 4.21-4.17 (m, 3H), 3.94 (s, 2H), 3.73 (m, 2H), 3.11 (m, 2H), 1.49-1.44 (m, 2H), 1.17-1.12 (m, 2H). MS (ESI): m / z 484.4 [M+H] ⁺ .

The compounds in Table 9 below were prepared according to procedures similar to those described for compound (168) in Example 168. Table 9 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 169 N- (4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((tetrahydro- 2H -pyran-4-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 512.4 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.59 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 4.50 (s, 2H), 4.07 (s, 3H), 4.05-3.93 (m, 3H), 3.92 (s, 2H), 3.64 (t, J = 6.8 Hz, 2H), 3.39 (m, 2H), 3.00 (t, J = 6.8 Hz, 2H), 1.93 (br d, J = 10.8 Hz, 2H), 1.71 (m, 2H), 1.33-1.28 (m, 2H), 1.19 (br d, J = 3.8 Hz, 3H), 1.06-0.99 (m, 2H). 170 (R)- or (S)- N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((tetrahydrofuran-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate relative stereochemistry MS (ESI): m / z 498.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.30 (br s, 1H), 4.68 (d, J = 6.4 Hz,2H), 4.41-4.33 (m, 1H), 4.18-4.03 (m, 5H), 3.96-3.90 (m, 4H), 3.76 (m, 2H), 3.23 (m, 2H), 2.47 (m, 1H), 2.35-2.33 (m,1H), 1.57 (s, 2H), 1.06 (s, 2H). SFC R _t = 5.756 min, 100% ee, [CHIRALPAK IC-3, 5-40% EtOH (0.05% Et ₂ NH), 3 mL/min]. 171 (R)- or (S)- N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((tetrahydrofuran-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate relative stereochemistry MS (ESI): m / z 498.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.30 (s, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.38 (m, 1H), 4.19-4.14 (m, 5H), 4.02-3.90 (m, 4H), 3.75 (m, 2H), 3.23-3.19 (m, 2H), 2.45-2.42 (m, 1H), 2.34-2.31(m, 1H), 1.56-1.54 (m, 2H), 1.09-1.06 (m, 2H). SFC R _t = 9.621 min, 96% ee, [CHIRALPAK IC-3, 5-40% EtOH (0.05% Et ₂ NH), 3 mL/min]. Example 172 N- (4-Cyanobenzyl)-1-methyl-6-((1-((3-methyloxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (172)

Step 1: 1-Methyl-6-((1-((3-methyloxacyclobutan-3-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the procedure described in the synthesis of (int-11) with the exception that 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced with 3-((1-(bromomethyl)cyclopropyl)sulfonyl)-3-methyloxacyclobutane (int-40). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.23 (d, J = 6.8 Hz, 2H), 4.49 (d, J = 6.8 Hz, 2H), 4.23 (s, 3H), 3.92 (s, 2H), 3.72 (t, J = 6.8 Hz, 2H), 3.50 (s, 3H), 3.14 (br t, J = 6.8 Hz, 2H), 2.00 (s, 3H), 1.52-1.46 (m, 2H), 1.07-1.01 (m, 2H). MS (ESI): m / z 384.1 [M+H] ⁺ .

Step 2: N- (4-cyanobenzyl)-1-methyl-6-((1-((3-methyloxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (172) was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 1-methyl-6-((1-((3-methyloxacyclobutan-3-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.23 (d, J = 6.8 Hz, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.49 (d, J = 6.8 Hz, 2H), 4.15 (s, 3H), 3.91 (s, 2H), 3.69 (t, J = 6.8 Hz, 2H), 3.19 (t, J = 6.8 Hz, 2H), 2.00 (s, 3H), 1.52-1.45 (m, 2H), 1.06-0.98 (m, 2H). MS (ESI): m / z 498.4 [M+H] ⁺ . Example 173 N -(4-cyanobenzyl)-6-((1-((3-(hydroxymethyl)oxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (173)

Step 1: 1-methyl-7-oxo-6-((1-((3-(((triisopropylsilyl)oxy)methyl)oxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] pyridine-3-carboxylic acid ethyl ester was obtained using the procedure of intermediate (int-6), except that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5) was replaced by 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by ((3-((1-(bromomethyl)cyclopropyl)sulfonyl)oxycyclobutan-3-yl)methoxy)triisopropylsilane (int-41). TLC R _f = 0.5 (25% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.14-5.11 (m, 2H), 4.86 (d, J = 6.8 Hz, 2H), 4.42 (q, J = 7.2 Hz, 2H), 4.31 (s, 2H), 4.22 (s, 3H), 3.92 (s, 2H), 3.73 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H), 1.54-1.48 (m, 2H), 1.41 (t, J = 7.2 Hz, 3H), 1.18-1.10 (m, 24H), 1.08-1.03 (m, 3H).

Step 2: N- (4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((3-(((triisopropylsilyl)oxy)methyl)oxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 1, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-6) was replaced with 1-methyl-7-oxo-6-((1-((3-(((triisopropylsilyl)oxy)methyl)oxacyclobutan-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 670.1 [M+H] ⁺ .

Step 3: N- (4-cyanobenzyl)-6-((1-((3-(hydroxymethyl)oxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] Pyridine-3-carboxamide (173) was obtained using the method described in step 5 of Example 105, except that 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile was replaced with N -(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((3-(((triisopropylsilyl)oxy)methyl)oxacyclobutan-3-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (t, J = 6.2 Hz, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 5.83 (t, J = 5.6 Hz, 1H), 4.87 (d, J = 7.0 Hz, 2H), 4.64 (d, J = 7.0 Hz, 2H), 4.46 (br d, J = 6.4 Hz, 2H), 4.11 (s, 3H), 4.05 (br d, J = 5.6 Hz, 2H), 3.85 (s, 2H), 3.60 (br t, J = 6.8 Hz, 2H), 2.97 (br t, J = 6.8 Hz, 2H), 1.32-1.23 (m, 2H), 1.08-0.98 (m, 2H). MS (ESI): m / z 514.4 [M+H] ⁺ . Example 174 6-(( 1 -((3-(aminomethyl)oxacyclobutane-3-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (174)

Step 1: A solution of N- (4-cyanobenzyl)-6-((1-((3-(hydroxymethyl)oxacyclobutan-3-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (173) (13 mg, 0.03 mmol, 1.0 equiv), _Et3N (39 mg, 0.15 mmol, 5.0 equiv), DMAP (2 mg, 0.015 mmol, 0.5 equiv) and p -TsCl (17 mg, 0.09 mmol, 3.0 equiv) in DCM (0.2 mL) was stirred at 25 °C for 12 h. The mixture was diluted with water (2 mL) and extracted with DCM (3 x 2 mL), then the combined organic extracts were washed with brine (2 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by RP-HPLC to give (3-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)oxacyclobutan-3-yl)methyl 4-methylbenzenesulfonate. MS (ESI): m / z 668.3 [M+H] ⁺ .

Step 2: A mixture of (3-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)oxacyclobutan-3-yl)methyl 4-methylbenzenesulfonate (18 mg, 0.027 mmol, 1.0 equiv) and _NaN3 (4 mg, 0.054 mmol, 2.0 equiv) in DMF (0.5 mL) was stirred at 80 °C for 12 h. The mixture was diluted with water (2 mL) and extracted with EtOAc (3 x 2 mL), then the combined organic extracts were washed with brine (2 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by RP-HPLC to give 6-((1-((3-(azidomethyl)oxacyclobutan-3-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. MS (ESI): m / z 539.3 [M+H] ⁺ .

Step 3: A solution of 6-((1-((3-(azidomethyl)oxacyclobutan-3-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (12 mg, 0.26 mmol, 1.0 equiv) and _PPh3 (10 mg, 0.40 mmol, 1.5 equiv) in THF (0.5 mL) and _H2O (0.1 mL) was stirred at 25 °C for 5 h. The mixture was diluted with water (3 mL) and extracted with EtOAc (3 x 3 mL), then the combined organic extracts were washed with brine (3 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by RP-HPLC to give 6-((1-((3-(aminomethyl)oxacyclobutan-3-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (174). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.97 (t, J = 6.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 4.85 (d, J = 7.2 Hz, 2H), 4.73 (d, J = 6.8 Hz, 2H), 4.47 (br d, J = 6.2 Hz, 2H), 4.11 (s, 3H), 3.85 (s, 2H), 3.61 (br t, J = 6.6 Hz, 2H), 3.22 (s, 2H), 3.02-2.93 (m, 2H), 1.30-1.21 (m, 2H), 1.07-1.00 (m, 2H). MS (ESI): m / z 513.3 [M+H] ⁺ . Example 175 N -(4-Chlorobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (175)

Step 1: 1-Methyl-7-oxo-6-((1-((2,2,5-trimethyl-1,3-dioxane-5-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the procedure described in the synthesis of (int-11) with the exception that 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced with 5-((1-(bromomethyl)cyclopropyl)sulfonyl)-2,2,5-trimethyl-1,3-dioxane (int-42). MS (ESI): m / z 441.9 [M+H] ⁺ .

Step 2: N- (4-chlorobenzyl)-1-methyl-7-oxo-6-((1-((2,2,5-trimethyl-1,3-dioxane-5-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[ 3,4- ]pyridine-3-carboxamide was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-9) was replaced with 1-methyl-7-oxo-6-((1-((2,2,5-trimethyl-1,3-dioxan-5-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. MS (ESI): m / z 565.4 [M+H] ⁺ .

Step 3: To a stirred solution of N- (4-chlorobenzyl)-1-methyl-7-oxo-6-((1-((2,2,5-trimethyl-1,3-dioxan-5-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (70 mg, 0.124 mmol, 1.0 equiv) in MeOH (1 mL) at 25 °C was added concentrated HCl (12 M, 22 mg, 0.62 mmol, 5.0 equiv). The mixture was stirred at 25 °C for 12 h, then purified by RP-HPLC to give N- (4-chlorobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (175). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.38-7.31 (m, 4H), 4.52 (s, 2H), 4.26 (s, 2H), 4.16 (s, 3H), 4.01-3.95 (m, 2H), 3.93-3.87 (m, 2H), 3.77 (t, J = 6.8 Hz, 2H), 3.10 (t, J = 6.8 Hz, 2H), 1.58-1.51 (m, 2H), 1.43 (s, 3H), 1.17-1.08 (m, 2H). MS (ESI): m / z 525.4 [M+H] ⁺ .

The compounds in Table 10 below were prepared according to procedures similar to those described for compound (175) in Example 175. Table 10 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 176 N- (4-cyanobenzyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4 -c ]pyridine-3-carboxamide MS (ESI): m / z 516.5 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.71 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 4.61 (s, 2H), 4.26 (s, 2H), 4.17 (s, 3H), 4.00-3.95 (m, 2H), 3.92-3.86 (m, 2H), 3.77 (t, J = 6.8 Hz, 2H), 3.10 (t, J = 6.8 Hz, 2H), 1.58-1.52 (m, 2H), 1.43 (s, 3H), 1.16-1.10 (m, 2H). 177 ( S ) -N- (1-(4-chlorophenyl)ethyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 539.4 [M+H] ⁺ . ¹ H NMR (500 MHz, MeOH- d ₄ ) δ 8.43 (d, J = 8.1 Hz, NH), 7.38 (d, J = 8.3 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 5.16 (q, J = 6.9 Hz, 1H), 4.23 (s, 2H), 4.16 (s, 3H), 3.95 (d, J = 11.9 Hz, 2H), 3.87 (d, J = 11.8 Hz, 2H), 3.78-3.67 (m, 2H), 3.04 (t, J = 6.8 Hz, 2H), 1.58-1.49 (m, 5H), 1.40 (s, 3H), 1.13-1.05 (m, 2H). SFC _Rt = 2.35 min, 96% ee, (CHIRALCEL OJ-H, 20% EtOH, 5 mL/min). 178 ( R ) -N- (1-(4-chlorophenyl)ethyl)-6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 539.4 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 8.43 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.4 Hz, 2H), 5.16 (q, J = 7.1 Hz, 1H), 4.23 (s, 2H), 4.15 (s, 3H), 3.95 (d, J = 11.8 Hz, 2H), 3.87 (d, J = 11.8 Hz, 2H), 3.73 (t, J = 6.8 Hz, 2H), 3.04 (t, J = 6.9 Hz, 2H), 1.60-1.47 (m, 5H), 1.40 (s, 3H), 1.13-1.05 (m, 2H). SFC _Rt = 1.86 min, 98% ee, (CHIRALCEL OJ-H, 20% EtOH, 5 mL/min). Example 179 N- (4-cyanobenzyl)-6-((1-((1,3-dimethoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (179)

Step 1: 6-((1-((1,3-dihydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described in Example 175, Step 3, with the exception that N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((2,2,5-trimethyl-1,3-dioxan-5-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was replaced with 1-methyl-7-oxo-6-((1-((2,2,5-trimethyl-1,3-dioxan-5-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid. MS (ESI): m / z 402.1 [M+H] ⁺ .

Step 2: To a stirred solution of 6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (300 mg, 0.75 mmol, 1.0 equiv) in MeOH (5 mL) at 25 °C was added _SOCl2 (267 mg, 2.25 mmol, 3.0 equiv). The mixture was stirred at 80 °C for 12 h, then concentrated and pre-dissolved in DMF (5 mL) and purified by RP-HPLC to give methyl 6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.23 (s, 3H), 4.19 (s, 2H), 4.00-4.12 (m, 2H), 4.03-3.97 (m, 2H), 3.94 (s, 3H), 3.74 (t, J = 6.8 Hz, 2H), 3.13 (t, J = 6.8 Hz, 2H), 1.69-1.64 (m, 2H), 1.45 (s, 3H), 1.14-1.07 (m, 2H). MS (ESI): m / z 416.1 [M+H] ⁺ .

Step 3: To a stirred solution of methyl 6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (250 mg, 0.6 mmol, 1.0 equiv) in DMF (3 mL) at 25 °C was added NaH (60% in mineral oil, 48 mg, 1.2 mmol, 2.0 equiv). After 1 h at 25 °C, MeI (85 mg, 0.6 mmol, 1.0 equiv) was added and the mixture was stirred for another 1 h. The mixture was quenched with water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extracts were dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC to give methyl 6-((1-((1-hydroxy-3-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (MS (ESI): m / z 430.3 [M+H] ⁺ ) and methyl 6-((1-((1,3-dimethoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (MS (ESI): m / z 444.1 [M+H] ⁺ ).

Step 4: N- (4-cyanobenzyl)-6-((1-((1,3-dimethoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (179) was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1,3-dimethoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.16 (s, 5H), 3.78-3.72 (m, 4H), 3.68-3.61 (m, 2H), 3.41 (s, 6H), 3.17 (t, J = 6.8 Hz, 2H), 1.55-1.59 (m, 2H), 1.45 (s, 3H), 1.11-1.05 (m, 2H). MS (ESI): m / z 544.4 [M+H] ⁺ . Example 180 N- (4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (180)

Step 1: 6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid was obtained using the method described for the synthesis of intermediate (int-14) with the exception of 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl) In the present invention, 6-((1-((1-hydroxy-3-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester was replaced by 6-((1-((1-hydroxy-3-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester.

Step 2: N-(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (180) was obtained using the method described in Example 3, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl 6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid. MS (ESI): m / z 530.1 [M+H] ⁺ . Example 181 and Example 182 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (181) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (182)

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (181) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (182) are prepared by N -(4-Cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (180) was obtained by chiral SFC separation.

Unless otherwise indicated, the examples indicate relative stereochemistry. SFC: CHIRALPAK IC-3, 5-40% MeOH (0.05% _Et2NH ), 3 mL/min

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (181). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.69 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 4.59 (s, 2H), 4.20-4.13 (m, 5H), 3.99 (d, J = 11.6 Hz, 1H), 3.81 (d, J = 11.6 Hz, 1H), 3.77-3.66 (m, 4H), 3.41 (s, 3H), 3.08 (t, J = 6.8 Hz, 2H), 1.55-1.48 (m, 2H), 1.40 (s, 3H), 1.13-1.08 (m, 2H). MS (ESI): m / z 530.4 [M+H] ⁺ . SFC: ee % = 99 %, Rt = 5.932 min.

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-hydroxy-3-methoxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (182). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.69 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 4.59 (s, 2H), 4.21-4.13 (m, 5H), 3.99 (d, J = 11.6 Hz, 1H), 3.81 (d, J = 11.6 Hz, 1H), 3.77-3.65 (m, 4H), 3.41 (s, 3H), 3.08 (t, J = 6.8 Hz, 2H), 1.55-1.48 (m, 2H), 1.40 (s, 3H), 1.13-1.08 (m, 2H). MS (ESI): m / z 530.4 [M+H] ^{+ .} SFC: ee % = 98 %, Rt = 7.943 min. Example 183 6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (183)

Step 1: To a solution of ethyl 6-((1-((1,3-dihydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (3.40 g, 7.92 mmol, 1.0 equiv) in DCM (40 mL) was added _SOCl2 (1.7 mL, 23.75 mmol, 3.0 equiv). The reaction mixture was stirred at 25 °C for 3 h, then it was diluted with water (10 mL) and adjusted to pH 8-9 with saturated _NaHCO3 . The mixture was extracted with EtOAc (3 x 50 mL), washed with brine (50 mL), dried _{over Na2SO4} , filtered and concentrated. The crude material was purified by column chromatography ( _SiO2 , 10-50% EtOAc/petroleum ether) to give 1-methyl-6-((1-((5-methyl-2-oxathioxan-1,3,2-dioxathiocyclohexan-5-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (400 MHz, CDCl ₃ ) δ 5.32 (d, J = 11.2 Hz, 1H), 4.84 (d, J = 13.76 Hz, 2H), 4.51-4.39 (m, 5H), 4.26-4.22 (m, 6H), 4.18-4.13 (m, 1H), 3.99-3.91 (m, 1H), 3.80 (t, J = 6.8 Hz, 2H), 3.72 (t, J = 6.8 Hz, 1H), 3.19-3.11 (m, 3H), 1.79 (br d, J = 2.0 Hz, 2H), 1.46-1.40 (m, 5H), 1.37 (s, 3H), 1.29-1.23 (m, 2H). MS (ESI): m / z 476.2 [M+H] ⁺ .

Step 2: To a solution of ethyl 1-methyl-6-((1-((5-methyl-2-oxathioxan-1,3,2-dioxathiocyclohexan-5-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (2.40 g, 5.26 mmol, 1.0 equiv) in DCM (20 mL), MeCN (20 mL) and _H2O (1 mL) were added _NaIO4 (1.57 g, 7.36 mmol, 1.4 equiv) and _RuCl3 (109 mg, 0.526 mmol, 0.1 equiv). The reaction mixture was stirred at 25 °C for 2 h, then diluted with water (40 mL) and extracted with EtOAc (3 × 40 mL). The combined organic extracts were washed with brine (40 mL), dried over _{Na2SO4 ,} filtered and concentrated to give 1-methyl-6-((1-((5-methyl-2,2-dioxothiocyano-1,3,2-dioxathiocyanocyclohexan-5-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 492.0 [M+H] ⁺ .

Step 3: 6-((1-((1-azido-2-methyl-3-(thioxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester was obtained using the method described in Step 2 of Example 174, except that 4-methylbenzenesulfonic acid (3-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-3-carboxylic acid The 1-methyl-6-((1-((5-methyl-2,2-dioxo-1,3,2-dioxathiocyclohexane-5-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester was replaced with 1-methyl-6-((1-((5-methyl-2,2-dioxo-1,3,2-dioxathiocyclohexane-5-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 535.1 [M+H] ⁺ .

Step 4: 6-((1-((1-azido-2-methyl-3-(thioxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthetic intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 6-((1-((1-azido-2-methyl-3-(thioxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 507.2 [M+H] ⁺ .

Step 5: Hydrogenated 3-azido-2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridine-6( 7H was obtained using the method described in Example 26, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-((1-azido-2-methyl-3-(thioxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and hydrazine was replaced with 4-(aminomethyl)benzonitrile hydrochloride. MS (ESI): m / z 612.4 [M+H] ⁺ .

Step 6: A solution of 3-azido-2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropyl hydrosulfate (1.40 g, 2.26 mmol, 1.0 equiv) in MeOH (15 mL) at 25 °C was treated _{with H2SO4} (17 mg, 0.18 mmol, 0.08 equiv) and the reaction mixture was stirred at 60 °C for 2 h. The mixture was diluted with water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by column chromatography ( _SiO2 , 10-50% EtOAc/petroleum ether) to give 6-((1-((1-azido-3-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.96 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 5.53 (t, J = 5.0 Hz, 1H), 4.47 (d, J = 6.2 Hz, 2H), 4.17-4.04 (m, 5H), 3.91-3.67 (m, 6H), 3.63 (br t, J = 6.8 Hz, 3H), 2.98 (br t, J = 6.8 Hz, 2H), 1.39 (br s, 2H), 1.34 (s, 3H), 1.04 (br d, J = 1.8 Hz, 2H). MS (ESI): m / z 541.4 [M+H] ⁺ .

Step 7: 6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (183) was obtained using the method described in step 3 of the synthesis of intermediate (int-2), except that (((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methoxy)methyl)benzene (i2-b) was replaced by 6-((1-((1-azido-3-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.47 (d, J = 6.2 Hz, 2H), 4.15-4.09 (m, 5H), 3.83-3.77 (m, 1H), 3.74-3.68 (m, 1H), 3.62 (t, J = 6.8 Hz, 2H), 3.18 (d, J = 5.2 Hz, 1H), 3.09 (d, J = 13.8 Hz, 1H), 2.97 (br t, J = 6.8 Hz, 2H), 2.87 (d, J = 13.8 Hz, 1H), 1.37-1.32 (m, 2H), 1.29 (s, 3H), 1.06-0.96 (m, 2H). MS (ESI): m / z 515.4 [M+H] ⁺ .

The compounds in Table 11 below were prepared according to procedures similar to those described for compound (183) in Example 183. Table 11 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 184 (R)- or (S)-6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 515.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 4.47 (d, J = 6.2 Hz, 2H), 4.17-4.07 (m, 5H), 3.83-3.76 (m, 1H), 3.75-3.68 (m, 1H), 3.62 (t, J = 6.8 Hz, 2H), 3.17 (d, J = 5.0 Hz, 1H), 3.08 (d, J = 13.6 Hz, 1H), 2.97 (t, J = 6.6 Hz, 2H), 2.85 (d, J = 13.6 Hz, 1H), 1.36-1.31 (m, 2H), 1.29 (s, 3H), 1.02-0.95 (m, 2H). SFC R _t = 3.634 min, 96.3% ee [AmyCoat, 50% EtOH (0.05% Et ₂ NH), 3 mL/min]. 185 (R)- or (S)-6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 515.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.47 (d, J = 6.2 Hz, 2H), 4.17-4.05 (m, 5H), 3.84-3.76 (m, 1H), 3.75-3.68 (m, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.17 (d, J = 5.2 Hz, 1H), 3.08 (d, J = 13.6 Hz, 1H), 2.97 (br t, J = 6.8 Hz, 2H), 2.85 (d, J = 13.6 Hz, 1H), 1.37-1.31 (m, 2H), 1.29 (s, 3H), 0.99 (br d, J = 2.0 Hz, 2H). SFC R _t = 2.501 min, 100% ee [AmyCoat, 50% EtOH (0.05% Et ₂ NH), 3 mL/min]. 186 6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 524.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.84 (t, J = 6.4 Hz, 1H), 7.42-7.26 (m, 4H), 4.38 (d, J = 6.4 Hz, 2H), 4.16-4.06 (m, 5H), 3.82-3.77 (m, 1H), 3.74-3.69 (m, 1H), 3.62 (t, J = 6.8 Hz, 2H), 3.07 (d, J = 13.6 Hz, 1H), 2.97 (t, J = 6.8 Hz, 2H), 2.85 (d, J = 13.6 Hz, 1H), 1.36-1.31 (m, 2H), 1.29 (s, 3H), 1.00-0.95 (m, 2H). 187 (R)- or (S)-6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 524.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.83 (t, J = 6.4 Hz, 1H), 7.41-7.27 (m, 4H), 5.29 (br s, 1H), 4.38 (d, J = 6.4 Hz, 2H), 4.15-4.08 (m, 5H), 3.83-3.76 (m, 1H), 3.75-3.68 (m, 1H), 3.62 (t, J = 6.8 Hz, 2H), 3.08 (br d, J = 13.8 Hz, 1H), 2.98 (br t, J = 6.8 Hz, 2H), 2.85 (br d, J = 13.8 Hz, 1H), 1.59 (br s, 1H), 1.36-1.25 (m, 5H), 1.01-0.95 (m, 2H). SFC R _t = 2.506 min, 100% ee [CHIRALPAK AD-3, 5-40% i -PrOH (0.05% Et ₂ NH), 3 mL/min]. 188 (R)- or (S)-6-((1-((1-amino-3-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 524.4 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.83 (t, J = 6.4 Hz, 1H), 7.40-7.28 (m, 4H), 5.29 (br s, 1H), 4.38 (d, J = 6.2 Hz, 2H), 4.16-4.07 (m, 5H), 3.83-3.77 (m, 1H), 3.74-3.68 (m, 1H), 3.62 (t, J = 6.8 Hz, 2H), 3.08 (br d, J = 13.4 Hz, 1H), 2.98 (t, J = 6.8 Hz, 2H), 2.86 (br d, J = 13.8 Hz, 1H), 1.59 (br s, 2H), 1.36-1.31 (m, 2H), 1.29 (s, 3H), 1.02-0.96 (m, 2H). SFC R _t = 2.424 min, 100% ee [CHIRALPAK AD-3, 5-40% i -PrOH (0.05% Et ₂ NH), 3 mL/min]. Example 189 N-(4-Chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (189)

Step 1: 6-((1-((2-(2,2-dimethyl-1,3-dioxacyclopentane-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] pyridine-3-carboxylic acid ethyl ester was obtained using the procedure of intermediate (int-6), with the exception that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5) was replaced by 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by 4-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyl-1,3-dioxacyclopentane (int-43). TLC R _f = 0.5 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.57-4.45 (m, 1H), 4.40 (q, J = 7.2 Hz, 2H), 4.27-4.17 (m, 4H), 4.15-4.02 (m, 2H), 3.87-3.62 (m, 3H), 3.16-3.02 (m, 2H), 1.60 (td, J = 2.2, 4.1 Hz, 2H), 1.53 (s, 3H), 1.47 (s, 3H), 1.43-1.33 (m, 9H), 1.13-1.02 (m, 2H).

Step 2: N-(4-chlorobenzyl)-6-((1-((2-(2,2-dimethyl-1,3-dioxacyclopentane-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was obtained using the method described in Example 1, except that 6-((1-(cyclopropyl)- In the reaction mixture, ethyl 6-((1-((2-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-6) was replaced with ethyl 6-((1-((2-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate and 4-(aminomethyl)benzonitrile hydrochloride was replaced with 4-chlorophenyl)methanamine.

Step 3: N-(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was obtained using the method described in Step 3 of Example 175, except that N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-((2,2,5-trimethyl-1, In the present invention, N-(4-chlorobenzyl)-6-((1-((2-(2,2-dimethyl-1,3-dioxolatocyclopentan-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide is replaced with N-(4-chlorobenzyl)-6-((1-((2-(2,2-dimethyl-1,3-dioxolatocyclopentan-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. Example 190 and Example 191 ( S ) -N- (4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (190) and ( R ) -N- (4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (191)

( S )- N -(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (190) and ( R )- N -(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (191) was obtained by chiral SFC separation of N-(4-chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (189).

Stereochemistry is assigned by analogy with similar compounds of known stereochemistry as determined by X-ray crystallography.

SFC CHIRALPAK AD-3, 40% i -PrOH (0.05% Et ₂ NH), 3 mL/min.

( S ) -N- (4-Chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (190). MS (ESI): m / z 539.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.27 (m, 4H), 7.18 (br t, J = 6.1 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.27-4.22 (m, 1H), 4.19 (td, J = 3.6, 7.4 Hz, 1H), 4.16-4.09 (m, 4H), 3.89 (d, J = 3.9 Hz, 1H), 3.81 (br dd, J = 3.8, 7.2 Hz, 1H), 3.75-3.66 (m, 3H), 3.19 (t, J = 6.9 Hz, 2H), 2.37-2.26 (m, 1H), 1.61 (td, J = 2.5, 5.1 Hz, 2H), 1.57 (s, 3H), 1.50 (s, 3H), 1.09 (td, J = 2.5, 4.7 Hz, 2H). SFC: Rt =1.667 min, 99% ee.

(R ) -N- (4-Chlorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (191). MS (ESI): m / z 539.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.32 (d, J = 8.0 Hz, 2H), 7.32-7.27 (m, 3H), 7.17 (br t, J = 6.0 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.27-4.22 (m, 1H), 4.19 (td, J = 3.6, 7.4 Hz, 1H), 4.16-4.09 (m, 4H), 3.88 (d, J = 3.6 Hz, 1H), 3.84-3.77 (m, 1H), 3.70 (t, J = 6.9 Hz, 3H), 3.19 (t, J = 6.9 Hz, 2H), 2.27 (br s, 1H), 1.63-1.60 (m, 2H), 1.57 (s, 3H), 1.50 (s, 3H), 1.09 (td, J = 2.5, 4.7 Hz, 2H). SFC: Rt =2.095 min, 98% ee.

The amide analogs in Table 12 below were prepared according to procedures similar to those described for compounds 189-191 in Examples 189-191. Stereochemistry was assigned by analogy with similar compounds having known stereochemistry as determined by X-ray crystallography. Table 12 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 192 ( S ) -N- (4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 530.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66-7.62 (m, J = 8.3 Hz, 2H), 7.48-7.43 (m, J = 8.2 Hz, 2H), 7.34-7.27 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.28-4.21 (m, 1H), 4.19 (td, J = 3.4, 7.3 Hz, 1H), 4.15 (s, 3H), 4.14-4.09 (m, 1H), 3.88 (d, J = 3.6 Hz, 1H), 3.80 (br s, 1H), 3.75-3.65 (m, 3H), 3.18 (t, J = 6.9 Hz, 2H), 2.30 (br s, 1H), 1.61 (td, J = 2.6, 5.3 Hz, 3H), 1.57 (s, 3H), 1.50 (s, 3H), 1.09 (td, J = 2.3, 7.3 Hz, 2H). SFC R _t = 3.787 min, 100% ee [CHIRALCEL OD-3, 5-40% i -PrOH (0.05% Et ₂ NH), 3 mL/min] 193 ( R ) -N- (4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 530.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.68-7.60 (m, 2H), 7.49-7.42 (m, J = 8.2 Hz, 2H), 7.33-7.27 (m, 1H), 4.66 (d, J = 6.3 Hz, 2H), 4.28-4.22 (m, 1H), 4.19 (dd, J = 3.3, 7.4 Hz, 1H), 4.15 (s, 3H), 4.14-4.10 (m, 1H), 3.82 (dd, J = 3.3, 11.3 Hz, 1H), 3.74-3.66 (m, 3H), 3.18 (t, J = 6.8 Hz, 2H), 1.62 (td, J = 2.6, 5.1 Hz, 2H), 1.57 (s, 3H), 1.50 (s, 3H), 1.13-1.05 (m, 2H). SFC R _t = 4.074 min, 93% ee [CHIRALCEL OD-3, 5-40% i -PrOH (0.05% Et ₂ NH), 3 mL/min] Example 194 and Example 195 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (194) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (195)

Step 1: Ethyl 6-((1-((1-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate was obtained using the procedure of intermediate (int-6), except that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine -3-carboxylic acid ethyl ester (int-5) was replaced with 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced with 4-(1-((1-(bromomethyl)cyclopropyl)sulfonyl)cyclopropyl)-2,2-dimethyl-1,3-dioxacyclopentane (int-44). TLC R _f = 0.3 (75% EtOAc/petroleum ether). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.86 (t, J = 6.8 Hz, 1H), 4.49-4.34 (m, 2H), 4.23 (s, 3H), 4.20-4.13 (m, 2H), 4.10-4.02 (m, 1H), 3.77-3.66 (m, 3H), 3.21-3.02 (m, 2H), 1.55-1.46 (m, 4H), 1.44-1.41 (m, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 1.20-1.11 (m, 2H), 1.08-0.94 (m, 2H).

Step 2: N-(4-cyanobenzyl)-6-((1-((1-(2,2-dimethyl-1,3-dioxolacyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was obtained using the method described in Example 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl In the present invention, ethyl 6-((1-((1-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-6) was replaced with ethyl 6-((1-((1-(2,2-dimethyl-1,3-dioxacyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate.

Step 3: N-(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was obtained using the method described in Step 7 of Example 154, except that N-(4-chlorobenzyl)-1-methyl-6-((1-(N-methyl-N-(2,2,5-trimethyl-1,3- In the present invention, N-(4-cyanobenzyl)-6-((1-((1-(2,2-dimethyl-1,3-dioxolacyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide is replaced by N-(4-cyanobenzyl)-6-((1-((1-(2,2-dimethyl-1,3-dioxolacyclopentan-4-yl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.

Step 4: (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (194) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (195) was obtained by chiral SFC separation of N-(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.

Unless otherwise indicated, the examples indicate relative stereochemistry. SFC: CHIRALCEL OD-3, 5-40% EtOH (0.05% _Et2NH ), 3 mL/min

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (194). MS (ESI): m / z 528.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.33-7.27 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.32 (s, 1H), 4.27-4.19 (m, 1H), 4.16 (s, 3H), 4.15-4.08 (m, 1H), 3.86 (s, 1H), 3.75 - 3.58 (m, 4H), 3.17 (t, J = 6.8 Hz, 2H), 2.50 (s, 1H), 1.59-1.56 (m, 2H), 1.54-1.44 (m, 2H), 1.34-1.27 (m, 2H), 1.05-0.95 (m, 2H). SFC: Rt=3.380 min, ee=100%,

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (195). MS (ESI): m / z 528.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.34-7.27 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.38-4.28 (m, 1H), 4.26-4.19 (m, 1H), 4.16 (s, 3H), 4.15-4.08 (m, 1H), 3.86 (s, 1H), 3.66 (t, J = 6.8 Hz, 4H), 3.17 (t, J = 6.8 Hz, 2H), 2.50 (s, 1H), 1.58 (s, 2H), 1.55-1.46 (m, 2H), 1.32 (s, 2H), 1.05-0.96 (m, 2H). SFC: Rt=3.492 min, ee=96%,

The amide analogs in Table 13 below were prepared according to procedures similar to those described for compounds (194) and (195) in Examples 194-195. Table 13 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 196 (R)- or (S)- N -(4-chlorobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 537.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.29 (m, 4H), 7.20 (t, J = 6.0 Hz, 1H), 4.58 (d, J = 6.2 Hz, 2H), 4.39-4.30 (m,1H), 4.28-4.20 (m, 1H), 4.18-4.09 (m, 4H), 3.93 (br s, 1H), 3.77-3.59 (m, 4H), 3.26-3.15 (m, 2H), 2.53 (s, 1H), 1.60-1.49(m, 4H), 1.39-1.28 (m, 2H), 1.08-0.94 (m, 2H). SFC R _t = 3.455 min, 100% ee [CHIRALCEL OD-3, 5-40% EtOH (0.05% Et ₂ NH), 3 mL/min]. 197 (R)- or (S)- N -(4-chlorobenzyl)-6-((1-((1-(1,2-dihydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 537.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.29 (m, 4H), 7.19 (t, J = 6.0 Hz, 1H), 4.58 (d, J = 6.2 Hz, 2H), 4.40-4.31 (m,1H), 4.28-4.20 (m, 1H), 4.16 (s, 4H), 3.91 (d, J = 3.6 Hz, 1H), 3.77-3.58 (m, 4H), 3.24-3.10 (m, 2H), 2.58-2.36 (m, 1H), 1.59-1.48 (m, 4H), 1.33 (d, J = 2.4 Hz, 2H), 1.07-0.94 (m, 2H). SFC R _t = 3.559 min, 93% ee [CHIRALCEL OD-3, 5-40% EtOH (0.05% Et ₂ NH), 3 mL/min]. Example 198 (R)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (198)

_Et3N (4.0 equiv) was added to a solution of (R)-N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3- _carboxamide (193) (1.0 equiv) in _CH2Cl2 , followed by the addition of _TsCl (2.0 equiv) in one portion at room temperature. After 5 h, the solution was concentrated, redissolved in MeOH, and _K2CO3 (6.0 equiv) was added in one portion. The resulting suspension was stirred vigorously for 90 min, then concentrated. _The crude reaction mixture was partitioned between _CH2Cl2 and _H2O (5 mL each) and the aqueous layer was extracted (2 x 5 mL _CH2Cl2 ). The combined organic extracts were dried ( _MgSO4 ), filtered, and concentrated to give the desired crude _epoxide . _NH3 in methanol (7.0 equiv) was added to the crude epoxide and the solution was capped and heated to 60 °C for 2 h. The reaction mixture was concentrated to dryness and the crude solid was purified by RP-HPLC to give (R)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (198). MS (ESI): m / z 529.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 4.66 (d, J = 6.6 Hz, 2H), 4.28-4.17 (m, 2H), 4.15 (s, 3H), 3.98 (m, 1H), 3.77-3.67 (m, 2H), 3.18 (m, 2H), 3.00 (m, 1H), 2.67 (m, 1H), 1.63-1.60 (m, 2H), 1.51 (s, 3H), 1.44 (s, 3H), 1.14-1.03 (m, 2H). SFC: Rt=10.121 min, ee=100%, [CHIRALPAK IC-3, 5-35% EtOH (0.05% Et ₂ NH), 3 mL/min].

The compounds in Table 14 below were prepared according to procedures similar to those described for compound (198) in Example 198 using appropriate diols and amines. Table 14 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 199 (R)- or (S)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 529.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 4.66 (d, J = 6.6 Hz, 2H), 4.29-4.17 (m, 2H), 4.15 (s, 3H), 3.98 (m, 1H), 3.79-3.66 (m, 2H), 3.18 (t, J = 6.8 Hz, 2H), 3.01 (m, 1H), 2.67 (m, 1H), 1.61 (s, 3H), 1.52 (s, 3H), 1.44 (s, 3H), 1.11-1.02 (m, 2H). SFC R _t = 8.827 min, 100% ee [CHIRALPAK IC-3, 5-35% EtOH (0.05% Et ₂ NH), 3 mL/min]. 200 (R)- or (S)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 538.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.29 (m, 4H), 7.19 (t, J = 6.2 Hz, 1H), 4.58 (d, J = 6.2 Hz, 2H), 4.32-4.18 (m, 2H), 4.15 (s, 3H), 3.98 (m, 1H), 3.80-3.66 (m, 2H), 3.20 (m, 2H), 3.00 (m, 1H), 2.68 (m, 1H), 1.62 (m, 2H), 1.53 (s, 3H), 1.45 (s, 3H), 1.14-1.05 (m, 2H). SFC R _t = 3.467 min, 100% ee [CHIRALPAK IC-3, 40% MeOH (0.05% Et ₂ NH), 3 mL/min]. 201 (R)- or (S)-6-((1-((4-amino-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 538.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.35-7.28 (m, 4H), 7.17 (m, 1H), 4.57 (d, J = 6.2 Hz, 2H), 4.30-4.17 (m, 2H), 4.14 (s, 3H), 3.97 (m, 1H), 3.77-3.66 (m, 2H), 3.19 (m, 2H), 2.99 (m, 1H), 2.67 (m, 1H), 1.52 (s, 4H), 1.44 (s, 3H), 1.13-0.99 (m, 2H). SFC R _t = 3.959 min, 100% ee [CHIRALPAK IC-3, 40% MeOH (0.05% Et ₂ NH), 3 mL/min]. 202 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate relative stereochemistry MS (ESI): m / z 543.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.95 (t, J = 6.3 Hz, 1H), 8.48 (s, 1H), 8.36 (s, 1H), 7.87-7.72 (m, 2H), 7.52-7.42 (m, 2H), 6.23 (s, 1H), 4.46 (d, J = 6.2 Hz, 2H), 4.10 (d, J = 6.4 Hz, 6H), 3.25 (d, J = 12.1 Hz, 1H), 3.06-2.94 (m, 3H), 2.60 (t, J = 5.4 Hz, 3H), 1.47 (s, 3H), 1.37 (s, 5H), 1.12-0.99 (m, 2H). 203 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate relative stereochemistry MS (ESI): m / z 543.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.97 (t, J = 6.3 Hz, 1H), 8.47 (s, 1H), 8.36 (s, 1H), 7.85-7.76 (m, 2H), 7.49 (d, J = 8.1 Hz, 2H), 6.23 (s, 1H), 4.48 (d, J = 6.3 Hz, 2H), 4.12 (d, J = 6.6 Hz, 6H), 3.25 (s, 2H), 3.01 (q, J = 7.6, 6.9 Hz, 3H), 2.62 (t, J = 5.4 Hz, 3H), 1.48 (s, 3H), 1.39 (s, 5H), 1.13-1.02 (m, 2H). 204 (R)- or (S)- N -(4-chlorobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate relative stereochemistry MS (ESI): m / z 552.4 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.85 (t, J = 6.3 Hz, 1H), 8.47 (s, 1H), 8.35 (s, 1H), 7.48-7.25 (m, 4H), 4.37 (d, J = 6.3 Hz, 2H), 4.10 (s, 5H), 3.74-3.55 (m, 2H), 3.23 (s, 1H), 3.02-2.89 (m, 2H), 2.60 (t, J = 5.4 Hz, 3H), 1.47 (s, 3H), 1.37 (s, 5H), 1.18-0.86 (m, 2H). 205 (R)- or (S)- N -(4-chlorobenzyl)-6-((1-((3-hydroxy-2-methyl-4-(methylamino)butan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate relative stereochemistry MS (ESI): m / z 552.2 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.85 (t, J = 6.3 Hz, 1H), 8.49 (s, 1H), 8.36 (s, 1H), 7.40-7.34 (m, 2H), 7.34-7.26 (m, 2H), 4.37 (d, J = 1.47 ​ (s, 3H), 1.37 (s, 5H), 1.14-0.97 (m, 2H). 206 (R)- or (S)- N -(4-chlorobenzyl)-6-((1-((4-(dimethylamino)-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 566.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.26-7.20 (m, 4H), 7.08 (s, 1H), 4.49 (d, J = 6.2 Hz, 2H), 4.26-4.11 (m, 2H), 4.06 (s, 3H), 4.01 (m, 1H), 3.70-3.62 (m, 3H), 3.10 (m, 2H), 2.35-2.30 (m, 1H), 2.27 (s, 6H), 1.43 (s, 3H), 1.29 (s, 3H), 1.19 (s, 2H), 0.99 (s, 2H). SFC R _t = 5.728 min, 85% ee [CHIRALPAK IC-3, 40% EtOH (0.05% Et ₂ NH), 3 mL/min]. 207 (R)- or (S)- N -(4-chlorobenzyl)-6-((1-((4-(dimethylamino)-3-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide Unless otherwise indicated, the examples indicate the relative stereochemistry MS (ESI): m / z 566.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.34-7.28 (m, 4H), 7.16 (s, 1H), 4.57 (d, J = 6.2 Hz, 2H), 4.37-4.18 (m, 2H), 4.14 (s, 3H), 4.10 (m, 1H), 3.78-3.68 (m, 3H), 3.21-3.13 (m, 2H), 2.43 (s, 1H), 2.37 (s, 6H), 1.52 (s, 2H), 1.37 (s, 3H), 1.26 (d, J = 3.8 Hz, 2H), 1.08 (d, J = 2.2 Hz, 2H). SFC R _t = 4.907 min, 100% ee [CHIRALPAK IC-3, 40% EtOH (0.05% Et ₂ NH), 3 mL/min]. 208 6-((1-((1-(2-amino-1-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 527.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.2 Hz, 2H), 7.45 (d, J = 8.2 Hz, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.27 (d, J = 14.4 Hz, 1H), 4.16 (s, 3H), 4.13-4.04 (m, 2H), 3.73-3.62 (m, 2H), 3.22-3.12 (m, 2H), 2.96 (dd, J = 3.6, 12.7 Hz, 1H), 2.69 (dd, J = 9.2, 12.6 Hz, 1H), 1.61-1.38 (m, 4H), 1.31-1.11 (m, 3H), 1.10-0.94 (m, 2H). 209 6-((1-((1-(2-amino-1-hydroxyethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 536.2 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.36-7.28 (m, 4H), 7.18 (br t, J = 6.1 Hz, 1H), 4.57 (d, J = 6.1 Hz, 2H), 4.28 (d, J = 14.4 Hz, 1H), 4.15 (s, 3H), 4.12-4.04 (m, 2H), 3.75-3.60 (m, 2H), 3.30-3.08 (m, 2H), 2.93 (dd, J = 4.0, 12.7 Hz, 1H), 2.67 (dd, J = 8.8, 12.6 Hz, 1H), 1.49-1.37 (m, 4H), 1.30-0.96 (m, 4H). Example 210 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentane-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (210)

Step 1: To a solution of N-(4-cyanobenzyl)-1-methyl-6-((1-((2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (1.0 g, 2.01 mmol, 1.0 equiv) in THF (10 mL) was added prop-1-en-2-ylmagnesium bromide (584 mg, 4.02 mmol, 2.0 equiv) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h, then the solution was quenched with saturated _NH4Cl (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried _{over Na2SO4} , filtered and concentrated. The residue was purified by RP-HPLC to give (N-(4-cyanobenzyl)-6-((1-((3-hydroxy-2,4-dimethylpent-4-en-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.94 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 5.61 (d, J = 3.8 Hz, 1H), 5.00 (br s, 2H), 4.47 (d, J = 6.4 Hz, 3H), 4.26-4.17 (m, 1H), 4.14-4.06 (m, 4H), 3.67-3.57 (m, 2H), 3.10-2.95 (m, 2H), 1.80-1.70 (m, 3H), 1.45 (s, 3H), 1.38 (d, J = 5.4 Hz, 2H), 1.16 (s, 3H), 0.98 (t, J = 5.4 Hz, 2H). MS (ESI): m / z 540.0 [M+H] ⁺ .

Step 2: To a solution of N-(4-cyanobenzyl)-6-((1-((3-hydroxy-2,4-dimethylpent-4-en-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (650 mg, 1.20 mmol, 1.0 equiv) in EtOH (10 mL) at 25 °C were added cobalt catalyst (22 mg, 0.06 mmol, 0.05 equiv) and di-tert-butyl azodicarboxylate (416 mg, 1.81 mmol, 1.5 equiv). The reaction mixture was stirred at 25 °C for 10 min, then _PhSiH3 (130 mg, 1.20 mmol, 1.0 eq) was added and the mixture was stirred at 25 °C for another 2 h. The reaction was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried _{over Na2SO4} , filtered and concentrated. The mixture was purified by RP-HPLC to give di-tert-butyl 1-(4-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-3-hydroxy-2,4-dimethylpentan-2-yl)hydrazine-1,2-dicarboxylate. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.95 (br t, J = 6.2 Hz, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 4.47 (d, J = 6.2 Hz, 2H), 4.25-4.15 (m, 1H), 4.11 (s, 3H), 3.63 (br d, J = 5.2 Hz, 2H), 2.98 (br s, 2H), 1.55-1.22 (m, 35H). MS (ESI): m / z 572.5 [M-2Boc+H] ⁺ .

Note: Cobalt catalyst was obtained using the method described by: Waser, J.; Gaspar, B.; Nambu, H.; Carreira, EM Hydrazines and azides via the metal-catalyzed hydrohydrazination and hydroazidation of olefins J. Am. Chem. Soc. 2006, 128 , 11693-11712)

Step 3: To a solution of di-tert-butyl 1-(4-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)methyl)cyclopropyl)sulfonyl)-3-hydroxy-2,4-dimethylpentan-2-yl)hydrazine-1,2-dicarboxylate (500 mg, 0.65 mmol, 1.0 equiv) in DCM (5 mL) at 25°C was added TFA (1 mL). The reaction mixture was stirred at 25°C for 12 h, then it was diluted with water (10 mL) and the pH was adjusted to 8-9 _with saturated _Na2CO3 . The biphasic mixture was concentrated, then the residue was diluted in DMF (10 mL) and the solids were removed by filtration. The filtrate was purified by RP-HPLC to give (N-(4-cyanobenzyl)-6-((1-((4-hydrazino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.93 (t, J = 6.2 Hz, 1H), 7.79 (d, J = 8.2 Hz, 2H), 7.48 (d, J = 8.2 Hz, 2H), 5.73 (br s, 1H), 4.47 (d, J = 6.2 Hz, 2H), 4.23-4.15 (m, 1H), 4.11 (s, 4H), 4.07-4.01 (m, 1H), 3.69-3.58 (m, 2H), 2.98 (br t, J = 6.8 Hz, 2H), 1.53-1.45 (m, 3H), 1.42-1.31 (m, 5H), 1.14 (s, 3H), 1.03-0.90 (m, 5H). MS (ESI): m / z 572.5 [M+H] ⁺ .

Step 4: Zn powder (30 g) was activated by stirring with 5% HCl (40 mL) for 3 min, then the solid was isolated by filtration and washed with water (3 x 40 mL), acetone (2 x 30 mL), and _Et2O (2 x 30 mL), then dried under high vacuum for 2 h. A portion of this activated Zn powder (114 mg, 1.75 mmol, 10.0 equiv) was added to a solution of N-(4-cyanobenzyl)-6-((1-((4-hydrazino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (100 mg, 0.175 mmol, 1.0 equiv) in AcOH (5 mL) at 25 °C, followed by acetone (0.1 mL) after 10 min. The reaction was stirred at 25 °C for 1 h, followed by 11 h at 60 °C. The reaction mixture was quenched with saturated NaHCO ₃ (10 mL) and the mixture was extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. The residue was purified by RP-HPLC to give 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (210). ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.71 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 4.61 (s, 3H), 4.32-4.20 (m, 2H), 4.18 (s, 3H), 3.91 (s, 1H), 3.76 (dt, J = 3.1, 6.8 Hz, 2H), 3.37 (s, 1H), 3.11 (t, J = 6.8 Hz, 2H), 1.62 (d, J = 16.0 Hz, 6H), 1.60-1.54 (m, 2H), 1.30 (s, 3H), 1.25 (s, 3H), 1.17-1.05 (m, 2H). MS (ESI): m / z 557.5 [M+H] ⁺ . Example 211 and Example 212 (R)- or (S)- 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)- N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (211) and (R)- or (S)- 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)- N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (212)

(R)- or (S)- 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)- N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]pyridine-3-carboxamide (211) and (R)- or (S)- 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)- N -(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1 H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (212) was obtained by chiral SFC separation of 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (210).

Unless otherwise indicated, the examples indicate relative stereochemistry. SFC: CHIRALPAK IC-3, 60% MeOH (0.05% _Et2NH ), 3 mL/min.

(R)- or (S)- 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (211). MS (ESI): m / z 557.5 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.69 (d, J = 8.0 Hz, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.59 (s, 2H), 4.29-4.11 (m, 5H), 3.90 (s, 1H), 3.78-3.69 (m, 2H), 3.37-3.33 (m, 1H), 3.09 (t, J = 6.8 Hz, 2H), 1.62 (s, 3H), 1.58 (s, 3H), 1.55-1.50 (m, 2H), 1.29 (s, 3H), 1.24 (s, 3H), 1.12-1.06 (m, 2H). SFC: Rt = 1.071 min, 98% ee.

(R)- or (S)- 6-((1-((4-amino-3-hydroxy-2,4-dimethylpentan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (212). MS (ESI): m / z 557.5 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.59 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 4.49 (s, 2H), 4.20-4.02 (m, 5H), 3.80 (s, 1H), 3.69-3.57 (m, 2H), 3.25 (s, 1H), 2.99 (t, J = 6.8 Hz, 2H), 1.52 (s, 3H), 1.47 (s, 3H), 1.45-1.40 (m, 2H), 1.19 (s, 3H), 1.14 (s, 3H), 1.03-0.95 (m, 2H). SFC: Rt = 1.754 min, 96% ee. Example 213 (R)-6-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (213)

Step 1: ( R )-4-(2-((1-((3-(ethoxycarbonyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester was obtained using the procedure of intermediate (int-6), except that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5) was replaced by 1-methyl-7-oxo-4,5, 6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-10) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) were replaced with (R)-4-(2-((1-(bromomethyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (int-45). MS (ESI): m / z 583.7 [M+H] ⁺ .

Step 2: ( R )-6-((1-((2-(3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid was obtained using the method described for the synthesis of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H -pyrazolo[3,4-c ]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by (R)-6-((1-((2-(3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by ( R )-6-((1-((2-(3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine )-tert-butyl 4-(2-((1-((3-(ethoxycarbonyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate. MS (ESI): m / z 555.6 [M+H] ⁺ .

Step 3: ( R )-4-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with ( R) -4-(2 ... )-6-((1-((2-(3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. MS (ESI): m / z 669.6 [M+H] ⁺ .

Step 4: A solution of ( R )-tert-butyl 4-(2-((1-((3-((4-cyanobenzyl)aminocarbonyl)-1-methyl-7-oxo-4,5-dihydro- 1H -pyrazolo[3,4- c ]pyridin-6( 7H )-yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (55 mg, 0.082 mmol, 1.0 equiv) in TFA (2.5 mL) was stirred at room temperature for 5 min and then concentrated. The residue was dissolved in MeOH (2 mL), filtered and purified by RP-HPLC to give ( R )-6-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (213). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.94 (t, J = 6.1 Hz, 1H), 7.78 (d, J = 7.5 Hz, 2H), 7.47 (d, J = 7.9 Hz, 2H), 4.68 (s, 1H), 4.46 (d, J = 6.0 Hz, 2H), 4.11 (s, 5H), 3.67 (s, 1H), 3.61 (t, J = 6.6 Hz, 2H), 3.18 (s, 1H), 2.97 (t, J = 6.5 Hz, 2H), 1.42 (s, 3H), 1.37 (s, 3H), 1.35-1.30 (m, 2H), 1.04-0.96 (m, 2H). MS (ESI): m / z 529.1 [M+H] ⁺ . Example 214 ( R )-6-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide hydrochloride (214)

Step 1: (R)-4-(2-((1-((3-((4-chlorobenzyl)aminoformyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester was obtained using the method described in Example 3, with the exception of 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester. 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced by (R)-6-((1-((2-(3-(tert-butoxycarbonyl)-2,2-dimethyloxazolidin-4-yl)propan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid and 4-(aminomethyl)benzonitrile hydrochloride was replaced by (4-chlorophenyl)methanamine. MS (ESI): m / z 678.6 [M+H] ⁺ .

Step 2: A suspension of tert-butyl ((R)-4-(2-((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)propan-2-yl)-2,2-dimethyloxazolidine-3-carboxylate (55 mg, 0.081 mmol, 1.0 equiv) in MeOH (1.5 mL) was cooled to 0 °C and then washed with AcCl (150 µL, 2.110 mmol) over several minutes with efficient stirring. mmol, 26.0 equiv) dropwise. The resulting suspension was stirred at room temperature for 1 h and then concentrated. The residue was suspended in EtOAc (2 mL) and the solid product was collected by filtration, washed with EtOAc (2 × 2 mL) and dried to give ( R )-6-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl) -N- (4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide hydrochloride (214). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.85 (t, J = 6.2 Hz, 1H), 8.04 (s, 3H), 7.37 (d, J = 7.7 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 5.52 (s, 1H), 4.37 (d, J = 5.9 Hz, 2H), 4.10 (s, 3H), 4.09 (s, 2H), 3.88 (d, J = 10.2 Hz, 1H), 3.70-3.58 (m, 3H), 2.98 (t, J = 6.5 Hz, 2H), 1.58 (s, 3H), 1.54 (s, 3H), 1.40 (s, 2H), 1.12 (s, 2H). MS (ESI): m / z 538.5 [M+H] ⁺ . Example 215 ((1-((3-((4-chlorobenzyl)aminomethyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro- 6H -pyrazolo[3,4- c ]pyridin-6-yl)methyl)cyclopropyl)sulfonyl) -D -valeric acid (215)

Step 1: A solution of (R)-6-((1-((3-amino-4-hydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-N-(4-chlorobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (214) (42 mg, 0.073 mmol, 1.0 equiv) and DIEA (0.128 mL, 0.731 mmol, 10.0 equiv) in _CH2Cl2 (1.5 mL) was treated with _Boc2O (0.026 mL, 0.110 mmol, _1.5 equiv), stirred at room temperature overnight, and then dry loaded onto SiO ₂ and purified by column chromatography (SiO ₂ , 0-100% EtOAc/heptane) to give (R)-tert-butyl(3-((1-((3-((4-chlorobenzyl)carbamyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-1-hydroxy-3-methylbutan-2-yl)carbamate. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.34-7.28 (m, 4H), 7.15 (d, J = 11.9 Hz, 1H), 5.59 (s, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.22 (d, J = 14.3 Hz, 1H), 4.13 (s, 3H), 4.10 (d, J = 14.2 Hz, 1H), 3.99-3.87 (m, 3H), 3.68 (h, J = 6.2, 5.8 Hz, 2H), 3.18 (q, J = 7.6, 7.2 Hz, 2H), 2.55 (s, 1H), 1.64 (d, J = 3.7 Hz, 6H), 1.45 (s, 9H), 1.34-1.27 (m, 2H), 1.13-1.02 (m, 2H). MS (ESI): m / z 538.5 [M+H] ⁺ .

Step 2: To a solution of (R)-tert-butyl(3-((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-1-hydroxy-3-methylbutan-2-yl)carbamate (38 mg, 0.0595 mmol, 1.0 equiv), NMO (86 mg, 0.731 mmol, 12.3 equiv) and water (0.013 mL, 0.731 mmol, 12.3 equiv) in MeCN (1 mL) was added TPAP (2.57 mg, 7.31 µmol, 0.123 equiv). The resulting solution was stirred at room temperature for 1 h, then quenched with i -PrOH (0.1 mL), diluted with water (5 mL) and acidified with saturated KHSO _4. The mixture was extracted with EtOAc (5 × 3 mL), then the combined organic extracts were washed twice with brine, dried over MgSO ₄ , filtered and concentrated. The residue was dry loaded onto _SiO2 and purified by column chromatography [ _SiO2 , 0-100% (3:1 EtOAc-EtOH + 1% AcOH)/heptane] to give (tert-butoxycarbonyl)((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-D-valeric acid. MS (ESI): m / z 652.6 [M+H] ⁺ .

Step 3: A solution of (tert-butoxycarbonyl)((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-D-valamine (16 mg, 0.0245 mmol, 1.0 equiv) in TFA (1 mL) was stirred at room temperature for 30 min and then concentrated. The residue was dissolved in 1:1 MeOH-DMSO (1.6 mL), filtered and purified by RP-HPLC to give ((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro- 6H -pyrazolo[3,4- c ]pyridin-6-yl)methyl)cyclopropyl)sulfonyl) -D -valamine (215) trifluoroacetate. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.85 (t, J = 6.3 Hz, 1H), 8.32 (s, 2H), 7.40-7.34 (m, 2H), 7.31 (d, J = 8.5 Hz, 2H), 4.37 (d, J = 6.3 Hz, 2H), 4.25 (s, 1H), 4.14 (d, J = 14.7 Hz, 1H), 4.10 (s, 3H), 4.04 (d, J = 14.7 Hz, 1H), 3.62 (t, J = 6.8 Hz, 2H), 2.99 (t, J = 6.8 Hz, 2H), 1.64 (s, 3H), 1.62 (s, 3H), 1.43 (q, J = 8.3, 6.5 Hz, 2H), 1.16 (td, J = 11.0, 6.3 Hz, 2H). MS (ESI): m / z 552.1 [M+H] ⁺ . Example 216 N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (216)

Step 1: Ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate was obtained using the procedure of intermediate (int-6), except that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced with ethyl 7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-46). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.86-4.76 (m, 2H), 4.42 (m, 2H), 4.10-4.02 (m, 4H), 3.76-3.70 (m, 2H), 3.13 (m, 2H), 2.72-2.60 (m, 1H), 1.53-1.49 (m, 2H), 1.40 (m, 3H), 1.27-1.24 (m, 2H), 1.10-1.06 (m, 4H), 0.99-0.90 (m, 21H). MS (ESI): m / z 568.1 [M+H] ⁺ .

Step 2: N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 1, with the exception that ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-6) was replaced with ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 7.31 (m, 1H), 4.72 (m, 2H), 4.67 (d, J = 6.4 Hz, 2H), 4.07 (s, 2H), 4.06 (m, 2H), 3.74 (m, 2H), 3.21 (m, 2H), 2.70 (m, 1H), 1.52 (m, 2H), 1.25 (m, 2H), 1.06 (m, 21H). MS (ESI): m / z 654.3 [M+H] ⁺ .

Step 3: To a solution of N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (140 mg, 0.21 mmol, 1.0 equiv) in THF (2 mL) was added TBAF (1.0 M in THF, 1.1 mL, 1.1 mmol, 5.0 equiv) at 25 °C. The reaction mixture was stirred at 25 °C for 2 h, then it was diluted with EtOAc (10 mL) and concentrated in vacuo. The residue was purified by RP-HPLC to give N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (216). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.32 (m, 1H), 4.73 (m, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.08 (s, 2H), 4.02 (m, 2H), 3.78 (m, 2H), 3.31 (m, 1H), 3.23 (m, 2H), 2.82 (m, 1H), 1.54 (m, 2H), 1.25 (m, 2H), 1.10 (m, 2H), 1.05 (m, 2H). MS (ESI): m / z 498.1 [M+H] ⁺ .

The compounds in Table 15 below were prepared according to procedures similar to those described for compound (216) in Example 216. Table 15 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 217 N- (4-cyanobenzyl)-1-(2-hydroxyethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 512.0 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH- d ₄ ) δ 7.71 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 4.73 (m, 2H), 4.62 (s, 3H), 4.14 (s, 2H), 3.96 (m, 2H), 3.73-3.72 (m, 2H), 3.13 (t, J = 6.8 Hz, 2H), 1.62 (s, 3H), 1.44-1.42 (m, 2H), 1.43-1.40 (m, 2H), 1.15-1.13 (m, 2H), 0.95-0.93 (m, 2H). 218 N- (4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 507.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85-8.82 (m, 1H), 7.38-7.30 (m, 4H), 4.87-4.84 (m, 1H), 4.58-4.55 (m, 2H), 4.38 (d, J = 6.4 Hz, 2H), 4.03 (s, 2H), 3.77-3.75 (m, 2H), 3.68-3.64 (m, 2H), 3.01-2.94 (m, 3H), 1.27-1.25 (m, 2H), 1.09-1.08 (m, 2H), 1.02-1.00 (m, 4H). 219 N- (4-chlorobenzyl)-1-(2-hydroxyethyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 481.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.85-8.82 (m, 1H), 7.38-7.30 (m, 4H), 4.87-4.85 (m, 1H), 4.57-4.54 (m, 2H), 4.38 (d, J = 6.0 Hz, 2H), 3.97 (s, 2H), 3.78-3.75 (m, 2H), 3.67-3.63 (m, 2H), 3.11 (s, 3H), 3.00-2.97 (m, 2H), 1.29-1.26 (m, 2H), 1.10-1.07 (m, 2H). 220 N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 530.1 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (m, 2H), 7.46 (m, 2H), 7.30 (m, 1H), 4.72 (m, 2H), 4.66 (d, J = 6.4 Hz, 2H), 4.17 (s, 2H), 4.01 (m, 2H), 3.85 (s, 2H), 3.75 (m, 2H), 3.22 (m, 2H), 1.61 (m, 2H), 1.50 (s, 6H), 1.08 (m, 2H). 221 N-(4-chlorobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxyethyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide MS (ESI): m / z 539.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33 (m, 4H), 7.17 (m, 1H), 4.70 (m, 2H), 4.57 (d, J = 6.4 Hz, 2H), 3.99 (m, 2H), 3.85 (s, 2H), 3.74 (m, 2H), 3.23 (m, 2H), 1.61 (m, 2H), 1.50 (s, 6H), 1.12 (m, 2H). Example 222 N- (4-Chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (222)

Step 1: 6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] pyridine-3-carboxylic acid ethyl ester was obtained using the procedure of intermediate (int-6), except that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5) was replaced by 7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-46) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by 1-(bromomethyl)-1-((1-methylcyclopropyl)sulfonyl)cyclopropane (int-2). TLC R _f = 0.6 (50% EtOAc/petroleum ether). MS (ESI): m / z 582.4 [M+H] ⁺ .

Step 2: 1-(2-Hydroxyethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthesis of intermediate (int-14), with the exception that the reaction was at 40 °C and that ethyl 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-13) was replaced by ethyl 6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate. TLC R _f = 0.4 (50% EtOAc/petroleum ether). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 4.84 (br s, 1H), 4.57 (m, 2H), 4.04 (s, 2H), 3.74 (m, 2H), 3.63 (m, 2H), 2.97 (m, 2H), 1.54 (s, 3H), 1.30-1.22 (m, 4H), 1.07-1.02 (m, 2H), 0.95-0.90 (m, 2H).

Step 3: 1-(2-(allyloxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described in Example 87, Step 1, except that ethyl 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate was replaced with 1-(2-hydroxyethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. MS (ESI): m / z 438.3 [M+H] ⁺ .

Step 4: 1-(2-(allyloxy)ethyl) -N- (4-chlorobenzyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 1-(2-(allyloxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and 4-(aminomethyl)benzonitrile hydrochloride was replaced with (4-chlorophenyl)methanamine. MS (ESI): m / z 561.4 [M+H] ⁺ .

Step 5: N- (4-chlorobenzyl)-1-(2-(2-hydroxyethoxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (222) was obtained using the method described in step 2 of the synthesis of intermediate (int-29), except that 1-(4-methoxybenzyl)-6-((1-((2-methylbut-3-en-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide was replaced with 1-(2-(allyloxy)ethyl) -N- (4-chlorobenzyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.37-7.27 (m, 5H), 4.75 (t, J = 5.4 Hz, 2H), 4.56 (d, J = 6.2 Hz, 2H), 4.12 (s, 2H), 3.89 (t, J = 5.2 Hz, 2H), 3.70 (t, J = 6.8 Hz, 2H), 3.67-3.61 (m, 2H), 3.61-3.55 (m, 2H), 3.19 (t, J = 6.8 Hz, 2H), 1.61 (s, 3H), 1.55-1.50 (m, 2H), 1.50-1.44 (m, 2H), 1.05-0.99 (m, 2H), 0.91-0.83 (m, 2H). MS (ESI): m / z 565.1 [M+H] ⁺ . Example 223 1-(2-(2-aminoethoxy)ethyl)-N-(4-chlorobenzyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (223)

Step 1: 1-(2-Hydroxyethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c]pyridine-3-carboxylic acid ethyl ester was obtained using the method described in Step 5 of Example 105, except that 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c ]pyridine-3-carboxylic acid ethyl ester was obtained using the method described in Step 5 of Example 105, except that 4-((4-(1-methyl-6-((1-((2-methyl-1-((triisopropylsilyl)oxy)propan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c ]pyridin-3-yl)-1H-1,2,3-triazol-1-yl)methyl)benzonitrile was replaced by 6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-((triisopropylsilyl)oxy)ethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. TLC R _f = 0.3 (50% EtOAc/petroleum ether). MS (ESI): m / z 426.3 [M+H] ⁺ .

Step 2: 1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] ethyl pyridine-3-carboxylate was obtained using the procedure described in the synthesis of (int-11), with the exception that ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-10) was replaced with ethyl 1-(2-hydroxyethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced with tert-butyl 1,2,3-thiazolidine-3-carboxylate 2,2-dioxide. MS (ESI): m / z 469.4 [M-Boc+H] ⁺ .

Step 3: 1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthesis of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 441.4 [M-Boc+H] ⁺ .

Step 4: (2-(2-(3-((4-chlorobenzyl)aminomethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c tert-butyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 1-(2-(2-((tert-butoxycarbonyl)amino)ethoxy)ethyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and 4-(aminomethyl)benzonitrile hydrochloride was replaced with (4-chlorophenyl)methanamine. MS (ESI): m / z 564.1 [M-Boc+H] ⁺ .

Step 5: 1-(2-(2-aminoethoxy)ethyl) -N- (4-chlorobenzyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (223) was obtained using the method described in Example 215, step 3, except that (tert-butoxycarbonyl)((1-((3-((4-chlorobenzyl)aminocarbonyl)-1-methyl-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-D-valeric acid was replaced with (2-(2-(3-((4-chlorobenzyl)aminocarbonyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c] pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-D-valeric acid. ] tert-butyl)pyridin-1-yl)ethoxy)ethyl)carbamate. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41 (br t, J = 6.2 Hz, 1H), 7.36-7.22 (m, 4H), 4.75 (t, J = 5.4 Hz, 2H), 4.58 (d, J = 6.2 Hz, 2H), 4.14 (s, 2H), 3.86 (t, J = 5.4 Hz, 2H), 3.71 (t, J = 6.8 Hz, 2H), 3.47 (t, J = 5.4 Hz, 2H), 3.20 (t, J = 6.8 Hz, 2H), 2.80 (t, J = 5.2 Hz, 2H), 1.63 (s, 3H), 1.58-1.45 (m, 4H), 1.08-1.00 (m, 2H), 0.92-0.85 (m, 2H). MS (ESI): m / z 564.2 [M+H] ⁺ . Example 224 N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (224)

Step 1: Ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate was obtained using the procedure of intermediate (int-6), except that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced with ethyl 1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-47). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.70-4.61 (m, 2H), 4.44-4.39 (m, 2H), 4.26-4.20 (m, 1H), 4.12-4.00 (m, 2H), 3.80-3.77 (m, 2H), 3.17-3.14 (m, 2H), 2.72-2.70 (m, 1H), 1.54-1.51 (m, 2H), 1.42-1.38 (m, 3H), 1.27-1.24 (m, 5H), 1.06-1.03 (m, 4H). MS (ESI): m / z 426.1 [M+H] ⁺ .

Step 2: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthetic intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester. MS (ESI): m / z 398.1 [M+H] ⁺ .

Step 3: N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (224) was obtained using the method described in Example 26, Step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced by 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and hydrazine was replaced by 4-(aminomethyl)benzonitrile hydrochloride. MS (ESI): m / z 512.2 [M+H] ⁺ . Example 225 and Example 226 (R)- or (S)- N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (225) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (226)

(R)- or (S)- N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (225) and (R)- or (S)- N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (226) was obtained by chiral SFC separation of N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.

Unless otherwise indicated, the examples indicate relative stereochemistry. SFC: CHIRALPAK AD-3, 5-40% i -PrOH (0.05% Et ₂ NH), 3 mL/min

(R)- or (S)- N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (225). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 4.68-4.65 (m, 2H), 4.63-4.62 (m, 1H), 4.53-4.51 (m, 1H), 4.20 (s, 1H), 4.15-4.01 (m, 2H), 3.79-3.76 (m, 2H), 3.35-3.34 (m, 1H), 3.25-3.18 (m, 2H), 2.81-2.75 (m, 1H), 1.54-1.51 (m, 2H), 1.27-1.23 (m, 5H), 1.13-1.04 (m, 2H), 1.04-1.00 (m, 2H). MS (ESI): m / z 512.3 [M+H] ⁺ . SFC: Rt=1.965 min, 100%ee

(R)- or (S)- N-(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (226). ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.30-7.29 (m, 1 H), 4.67-4.65 (m, 2H), 4.63-4.62 (m, 1H), 4.53-4.51 (m, 1H), 4.20 (s, 1H), 4.15-4.01 (m, 2H), 3.79-3.76 (m, 2H), 3.35-3.34 (m, 1H), 3.25-3.18 (m, 2H), 2.81-2.75 (m, 1H), 1.54-1.51 (m, 2H), 1.27-1.23 (m, 5H), 1.13-1.04 (m, 2H), 1.04-1.00 (m, 2H). MS (ESI): m / z 512.3 [M+H] ⁺ . SFC: Rt=2.140 min, 98% ee Example 227 N-(4-Cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-oxobutyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (227)

Step 1: Ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate was obtained using the procedure of intermediate (int-6), except that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced with ethyl 1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-49). ¹ H NMR (400 MHz, CDCl ₃ ) δ 4.77 (s, 2H), 4.41 (m, 2H), 4.08 (s, 2H), 3.88 (s, 2H), 3.83-3.75 (m, 2H), 3.16 (m, 2H), 2.74 (tt, J = 4.8, 8.0 Hz, 1H), 2.65 (m, 1H), 1.76-1.70 (m, 1H), 1.56-1.49 (m, 2H), 1.40 (m, 3H), 1.31-1.18 (m, 6H), 1.16-1.01 (m, 7H), 0.87-0.72 (m, 4H). MS (ESI): m / z 438.0 [M+H] ⁺ .

Step 2: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthetic intermediate (int-14), with the exception that ethyl 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-13) was replaced by ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate. MS (ESI): m / z 410.2 [M+H] ⁺ .

Step 3: N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-7-oxo-1-(2-oxobutyl)-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (227) was obtained using the method described in Example 3, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.24 (m, 1H), 5.34 (s, 2H), 4.65 (d, J = 6.0 Hz, 2H), 4.03 (s, 2H), 3.79 (t, J = 6.8 Hz, 2H), 3.24 (t, J = 6.8 Hz, 2H), 2.73-2.62 (m, 1H), 2.52 (q, J = 7.2 Hz, 2H), 1.53-1.47 (m, 2H), 1.27-1.18 (m, 2H), 1.12 (t, J = 7.2 Hz, 3H), 1.09-0.99 (m, 4H). MS (ESI): m / z 524.3 [M+H] ⁺ . Example 228 N -(4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (228)

N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]Pyridine-3-carboxamide (228) was obtained using the method described in Example 1, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-6) was replaced with 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-((1-hydroxycyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.27 (m, 1H), 4.70 (s, 2H), 4.67 (m, 2H), 4.09 (s, 2H), 3.79 (m, 2H), 3.24 (m, 2H), 2.85-2.75 (m, 1H), 1.55-1.50 (m, 2H), 1.29-1.20 (m, 2H), 1.12-1.06 (m, 2H), 1.06-1.01(m, 2H), 0.88-0.81 (m, 2H), 0.81-0.74 (m, 2H). MS (ESI): m / z 524.2 [M+H] ⁺ . Example 229 N -(4-Chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (229)

Step 1: Ethyl 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylate was obtained using the procedure of intermediate (int-6), except that ethyl 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-5) was replaced with ethyl 1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-51). MS (ESI): m / z 440.1 [M+H] ⁺ .

Step 2: N- (4-chlorobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (229) was obtained using the method described in Example 1, with the exception that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-6) was replaced with 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester and 4-(aminomethyl)benzonitrile hydrochloride was replaced with (4-chlorophenyl)methanamine. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.33-7.28 (m, 4 H), 7.16-7.13 (m, 1 H), 4.58-4.54 (m, 4 H), 4.07 (s, 2H), 3.87 (s, 1H), 3.79-3.75 (m, 2 H), 3.25-3.22 (m, 2 H), 2.74-2.69 (m, 1 H), 1.52-1.49 (m, 2 H), 1.25-1.17 (m, 8 H), 1.10-1.02 (m, 4 H). MS (ESI): m / z 535.2 [M+H] ⁺ .

The compounds in Table 16 below were prepared according to procedures similar to those described for compound (229) in Example 229. Table 16 Example/Compound No. Compound structure and name Physical data MS ( m/z ), ¹ H NMR 230 N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 526.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64-7.63 (m, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.29-7.21 (m, 1H), 4.66 (d, J = 6.4 Hz, 2H), 4.55 (s, 2H), 4.07 (s, 2H), 3.85 (s, 1H), 3.79-3.75 (m, 2H), 3.24-3.21 (m, 2H), 2.77-2.70 (m, 1H), 1.54-1.50 (m, 2H), 1.25-1.21 (m, 8H), 1.10-1.02 (m, 4H). 231 N- (4-chlorobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 509.1 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.81 (t, J = 6.2 Hz, 1H), 7.45-7.27 (m, 4H), 4.62 (s, 1H), 4.54 (s, 2H), 4.41 (m, 2H), 3.99 (s, 2H), 3.68 (m, 2H), 3.11 (s, 3H), 3.00 (br t, J = 6.8 Hz, 2H), 1.31-1.25 (m, 2H), 1.14-1.02 (m, 8H). 232 N- (4-cyanobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-(methylsulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 500.0 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.91 (t, J = 6.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 4.64 (br s, 1H), 4.55 (s, 2H), 4.50 (d, J = 6.0 Hz, 2H), 3.99 (s, 2H), 3.68 (t, J = 6.8 Hz, 2H), 3.11 (s, 3H), 3.04-2.94 (m, 2H), 1.34-1.22 (m, 2H), 1.17-1.01 (m, 8H). 233 N- (4-cyanobenzyl)-6-((1-(ethylsulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 514.4 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65-7.63 (m, 2H), 7.44 (d, J = 8.8 Hz, 2H), 4.66 (d, J = 6.0 Hz, 2 H), 4.55 (s, 2H), 3.96 (s, 2H), 3.81 (s, 1H), 3.77-3.75 (m, 2H), 3.28-3.20 (m, 4H), 1.54-1.53 (m, 2H), 1.40 (t, 3H), 1.22 (s, 6H), 1.05-1.01 (m, 2H). 234 N- (4-cyanobenzyl)-1-(2-hydroxy-2-methylpropyl)-6-((1-((1-(hydroxymethyl)cyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 556.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.65 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 4.67 (d, J = 6.4 Hz, 2H), 4.55 (s, 2H), 4.15 (s, 1H), 4.19-4.12 (m, 1H), 3.94 (s, 2H), 3.71 (m, 2H), 3.62 (br s, 1H), 3.22 (m, 2H), 2.89 (br s, 1H), 1.63-1.59 (m, 2H), 1.55-1.53 (m, 2H), 1.23 (s, 6H), 1.16-1.10 (m, 2H), 1.07-1.00 (m, 2H). 235 N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-1-(2-hydroxy-2-methylpropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide MS (ESI): m / z 558.3 [M+H] ⁺ . ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J = 8.4 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.31-7.30 (m, 1H), 4.68 (d, J = 6.4 Hz, 2H), 4.55 (s, 2H), 4.19 (s, 2H), 3.87 (s, 2H), 3.78-3.74 (m, 2H), 3.25-3.22 (m, 2H), 3.05 (br s, 1H), 1.62 (m, 2H), 1.52 (s, 6H), 1.24 (s, 6H), 1.10-1.06 (m, 2H). Example 236 N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (236)

Step 1: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (monomer) and 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid 3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(ethoxycarbonyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine c ]pyridin-1-yl)propyl ester (dimer) was obtained using the procedure of intermediate (int-6), with the exception that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-5) was replaced by 1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (int-53) 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (monomer). MS (ESI): m / z 426.1 [M+H] ⁺ . 3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-carboxylic acid 3-(6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-3-(ethoxycarbonyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-1-yl)propyl ester (dimer). MS (ESI): m / z 805.2 [M+H] ⁺ .

Step 2: 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthesis of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] pyridine-3-carboxylic acid ethyl ester (monomer) or 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] pyridin-1-yl)propyl ester (dimer). MS (ESI): m / z 398.1 [M+H] ⁺ .

Step 3: N- (4-cyanobenzyl)-6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (236) was obtained using the method described in Example 26, step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and hydrazine was replaced with 4-(aminomethyl)benzonitrile hydrochloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.66 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.32-7.30 (m, 1H), 4.73-4.67 (m, 4H), 4.10 (s, 2H), 3.80-3.77 (m, 2H), 3.51-3.43 (m, 3H), 3.25-3.22 (m, 2H), 2.90-2.87 (m, 1H), 2.10-2.08 (m, 2H), 1.55-1.54 (m, 2H), 1.26-1.24 (m, 2H), 1.12-1.10 (m, 2H), 1.06-1.04 (m, 2H). MS (ESI): m / z 512.2 [M+H] ⁺ . Example 237 N -(4-cyanobenzyl)-1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (237)

Step 1: 1-(3-Hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (monomer) and 1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid 3-(3-(ethoxycarbonyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-1-yl)propyl ester (dimer) was obtained using the procedure of intermediate (int-6), except that 1-methyl-7-oxo-6,7-dihydro-1H-pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (int-5) was replaced by 1-(3-hydroxypropyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] pyridine-3-carboxylic acid ethyl ester (int-53) and 1-(bromomethyl)-1-(cyclopropylsulfonyl)cyclopropane (int-1) was replaced by 1-(bromomethyl)-1-((1-methylcyclopropyl)sulfonyl)cyclopropane (int-2) 1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid ethyl ester (monomer). MS (ESI): m / z 440.1 [M+H] ⁺ . 3-(3-(ethoxycarbonyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-1-yl)propyl 1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-3-carboxylate (dimer). MS (ESI): m / z 833.3 [M+H] ⁺ .

Step 2: 1-(3-Hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid was obtained using the method described for the synthesis of intermediate (int-14), with the exception that 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester (int-13) was replaced by 1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ] pyridine-3-carboxylic acid ethyl ester (monomer) or 1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridin-1- yl )propyl ester (dimer). MS (ESI): m / z 412.1 [ M+H] ⁺ .

Step 3: N- (4-cyanobenzyl)-1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (237) was obtained using the method described in Example 26, step 1, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced with 1-(3-hydroxypropyl)-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxylic acid and hydrazine was replaced with 4-(aminomethyl)benzonitrile hydrochloride. ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.64 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.29 (m, 1H), 4.69-4.66 (m, 4H), 4.14 (s, 2H), 3.74-3.71 (m, 2H), 3.50-3.47 (m, 2H), 3.22-3.19 (m, 2H), 2.10-2.06 (m, 2H), 1.61 (s, 3H), 1.58-1.55 (m, 2H), 1.47-1.46 (m, 2H), 1.04-1.03 (m, 2H), 0.89-0.88 (m, 2H). MS (ESI): m / z 526.2 [M+H] ⁺ . Example 238 1-(2-(2-bromoethoxy)ethyl)-N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (238)

Step 1: A solution of N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (49) (100 mg, 0.206 mmol, 1.0 equiv) and 1-bromo-2-(2-bromoethoxy)ethane (47.8 mg, 0.206 mmol, 1.0 equiv) in DMF (1 _{mL) was treated with Cs2CO3 (} 134 mg, 0.412 mmol, 2.0 equiv). After 2 h at room temperature, the reaction mixture was diluted with saturated aqueous _NH4Cl and EtOAc, and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 5 mL) and the combined organic extracts were dried _{over Na2SO4} , filtered, and concentrated to give an oil. The residue was purified by column chromatography ( _SiO2 , 0-100%, EtOAc/heptane) to give 1-(2-(2-bromoethoxy)ethyl) -N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (238). ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.63 (d, J = 7.9 Hz, 2H), 7.45 (d, J = 7.9 Hz, 2H), 7.31 (d, J = 6.1 Hz, 1H), 4.75 (t, J = 5.3 Hz, 2H), 4.65 (d, J = 5.7 Hz, 2H), 4.16 (s, 2H), 3.90 (t, J = 5.3 Hz, 2H), 3.85 (d, J = 6.5 Hz, 2H), 3.72 (dt, J = 10.8, 6.3 Hz, 4H), 3.38 (t, J = 5.9 Hz, 2H), 3.18 (t, J = 6.8 Hz, 2H), 3.14 (d, J = 6.5 Hz, 1H), 1.59 (d, J = 2.4 Hz, 2H), 1.50 (s, 6H), 1.31-1.21 (m, 1H), 1.11-1.04 (m, 2H). MS (ESI): m/z 636.2 [M+H] ⁺ . Example 239 Ethylene glycol macrocyclic N -(4-cyanobenzyl)formamide (239)

Step 1: Ethyl 6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4 -c ]pyridine-3-carboxylate (int-29) (750 mg, 1.44 mmol, 1.0 equiv) and 1-bromo-2-(2-bromoethoxy)ethane (1.51 g, 6.50 mmol, 4.5 equiv) were dissolved in DMF (7.2 mL) and NaH (60% in mineral oil, 144 mg, 3.61 mmol, 2.5 equiv) was added at 23 °C (gas evolution). The mixture was sonicated for 20 min and then stirred for 20 min. The reaction mixture was diluted with saturated NH ₄ Cl and EtOAc, and the aqueous layer was then extracted with EtOAc (3 × 20 mL). The combined organic extracts were dried over MgSO ₄ , filtered, and concentrated. The residue was purified by column chromatography (SiO ₂ , 0-100% EtOAc/heptane) to give 6-((1-((1-(2-(2-bromoethoxy)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid ethyl ester. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.33 (d, J = 8.7 Hz, 2H), 6.81 (d, J = 8.8 Hz, 2H), 5.72 (s, 2H), 4.40 (q, J = 7.1 Hz, 2H), 4.15 (s, 2H), 3.81 (t, J = 6.1 Hz, 2H), 3.76 (s, 3H), 3.73 - 3.61 (m, 8H), 3.46 (t, J = 6.0 Hz, 2H), 3.07 (t, J = 6.9 Hz, 2H), 1.59 (d, J = 1.3 Hz, 2H), 1.55 (t, J = 3.6 Hz, 2H), 1.48 (s, 6H), 1.39 (t, J = 7.1 Hz, 3H), 1.09 - 0.99 (m, 2H). MS (ESI): m/z 670.5 [M+H] ⁺ .

Step 2: A solution of ethyl 6-((1-((1-(2-(2-bromoethoxy)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-1-(4-methoxybenzyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (510 mg, 0.760 mmol, 1.0 equiv) in TFA (3.5 mL) was stirred at 30 °C for 3 h. The mixture was diluted _{with CH2Cl2} (5 mL) and water (5 mL) and _basified to pH 10 with solid _Na2CO3 (gas evolution). The aqueous layer was extracted with EtOAc (3 x 4 mL), and the combined organic extracts were then dried over _MgSO4 , filtered, and concentrated to give ethyl 6-((1-((1-(2-(2-bromoethoxy)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate. ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.41 (q, J = 7.1 Hz, 2H), 4.21 (s, 2H), 3.87 - 3.62 (m, 16H), 3.48 (t, J = 6.0 Hz, 2H), 3.12 (t, J = 6.9 Hz, 2H), 1.61 - 1.57 (m, 3H), 1.49 (s, 7H), 1.41 (t, J = 7.1 Hz, 3H), 1.16 - 1.06 (m, 2H). MS (ESI): m/z 550.4 [M+H] ⁺ .

Step 3: A mixture of ethyl 6-((1-((1-(2-(2-bromoethoxy)ethoxy)-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (400 mg, 0.690 mmol, 1.0 equiv) and _Cs2CO3 ( ₇₄₃ mg, 2.281 mmol, 3.0 equiv) in DMF (100 mL) was stirred at room temperature for 16 h, then it was diluted with EtOAc (100 mL) and _H2O (50 mL). The aqueous layer was extracted with EtOAc (3 x 50 mL) and the combined organic extracts were dried _{over Na2SO4} , filtered, and concentrated. The product was purified by column chromatography ( _SiO2 , 50 → 100% EtOAc/heptane) to afford the ethylene glycol macrocyclic ethyl ester. ¹ H NMR (500 MHz, CDCl ₃ ) δ 4.41 (q, J = 7.1 Hz, 2H), 3.80 (s, 4H), 3.58 (d, J = 4.5 Hz, 5H), 3.18 (s, 2H), 1.61 (s, 2H), 1.45 (s, 6H), 1.39 (t, J = 7.1 Hz, 3H), 1.17 (s, 1H). MS (ESI): m/z 470.2 [M+H] ⁺ .

Step 4: Ethylene glycol macrocarboxylate was obtained using the method described for the synthetic intermediate (int-14), with the exception that ethyl 1-methyl-6-((1-((1-methylcyclopropyl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate (int-13) was replaced by ethylene glycol macrocarboxylate. MS (ESI): m / z 442.4 [M+H] ⁺ .

Step 5: Ethylene glycol macrocyclic N- (4-cyanobenzyl)carboxamide (239) was obtained using the method described in Example 3, except that 6-((1-(cyclopropylsulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid (int-11) was replaced by ethylene glycol macrocyclic carboxylic acid. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.91 (t, J = 6.3 Hz, 1H), 7.81-7.76 (m, 2H), 7.52-7.47 (m, 2H), 4.47 (d, J = 6.2 Hz, 2H), 3.71 (dd, J = 13.9, 6.4 Hz, 4H), 3.54 (s, 6H), 3.01 (t, J = 7.0 Hz, 2H), 1.41 (s, 2H), 1.32 (s, 6H), 1.21 (s, 2H). MS (ESI): m/z 556.5 [M+H] ⁺ . Example 240 Ethylene glycol macrocyclic N- (4-chlorobenzyl)formamide (240)

Ethylene glycol macrocyclic N- (4-chlorobenzyl)formamide (240) was obtained using the procedure described in Example 240, except that in step 5 4-(aminomethyl)benzonitrile was replaced by (4-chlorophenyl)methanamine. ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.82 (t, J = 6.4 Hz, 1H), 7.37 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 4.38 (d, J = 6.3 Hz, 2H), 3.76-3.64 (m, 4H), 3.53 (s, 6H), 3.37 (s, 4H), 3.00 (t, J = 7.0 Hz, 2H), 1.40 (s, 2H), 1.31 (s, 6H), 1.22 (d, J = 9.6 Hz, 3H). MS (ESI): m/z 565.5 [M+H] ⁺ . Example 241 Lactamide macrocyclic N- (4-cyanobenzyl)formamide (241)

Step 1: A solution of N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (49) (100 mg, 0.206 mmol, 1.0 equiv) and 1-bromo-2-(2-bromoethoxy)ethane (47.8 mg, 0.206 mmol, 1.0 equiv) in DMF (500 _µL ) was treated with _Cs2CO3 (134 mg, 0.412 mmol, 2.0 equiv) at room temperature. After 2 h, NaN ₃ (26.8 mg, 0.412 mmol, 2.0 eq) was added in one portion and the mixture was stirred at room temperature for 30 min, then at 40 °C for 12 h. Additional NaN ₃ (26.8 mg, 0.412 mmol, 2.0 eq) was added and the mixture was heated to 60 °C for 1 h, then diluted with H ₂ O (5 mL) and EtOAc (5 mL). The aqueous phase was extracted with EtOAc (3×5 mL) and the combined organic extracts were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography (SiO ₂ , 0-100%, EtOAc/heptane) to give 1-(2-(2-azidoethoxy)ethyl) -N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. MS (ESI): m/z 599.5 [M+H] ⁺ .

Step 2: 1-(2-(2-azidoethoxy)ethyl)-N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (80 mg, 0.134 mmol, 1.0 equiv) and NMO monohydrate (181 mg, 1.34 mmol, 10 equiv) were dissolved in MeCN (700 µL) followed by the addition of TPAP (3.76 mg, 10.69 µmol, 0.08 equiv) at room temperature. After 2 h, additional TPAP (3.76 mg, 10.69 µmol, 0.08 equiv) was added. After stirring for 1 hour, the reaction mixture was quenched with i- PrOH (100 µL) and concentrated. The residue was acidified to pH 3 with 2 M NaHSO ₄ and extracted with Et ₂ O (6 × 5 mL). The combined organic extracts were dried over Na ₂ SO ₄ , filtered, and concentrated to give an oil containing 2-((1-((1-(2-(2-azidoethoxy)ethyl)-3-((4-cyanobenzyl)carbamyl)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methyl An approximately 5:1 mixture of propionic acid and 1-(2-(2-azidoethoxy)ethyl)-N-(4-cyanobenzyl)-6-((1-((2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide.

Step 3: To a solution of the crude material from step 2, 2,3,4,5,6-pentafluorophenol (24.6 mg, 0.134 mmol, 1.0 eq) and DMAP (1.6 mg, 0.013 mmol, 0.1 eq) in CH2Cl2 (1 mL) was added EDC (38.4 mg, 0.200 mmol, 1.5 eq) in one portion at room temperature. After 1 h, the reaction mixture was diluted with _H2O (3 mL) and extracted _{with CH2Cl2} (3 x 5 mL). The combined organic extracts were dried _over MgSO4, filtered, and concentrated. The residue was purified by column chromatography (SiO ₂ , 0-100%, EtOAc/heptane) to give perfluorophenyl 2-((1-((1-(2-(2-azidoethoxy)ethyl)-3-((4-cyanobenzyl)carbamyl)-7-oxo-1,4,5,7-tetrahydro- 6H -pyrazolo[3,4- c ]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoate. ¹ H NMR (500 MHz, CDCl ₃ ) δ 7.70 - 7.56 (m, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.34 (s, 1H), 4.75 (d, J = 5.0 Hz, 2H), 4.64 (d, J = 6.2 Hz, 2H), 4.15 (s, 2H), 3.88 (d, J = 5.0 Hz, 2H), 3.71 (d, J = 7.7 Hz, 2H), 3.66 - 3.56 (m, 2H), 3.28 (d, J = 4.9 Hz, 2H), 3.18 (s, 2H), 1.91 (d, J = 3.7 Hz, 6H), 1.64 (s, 2H), 1.19 (s, 2H). MS (ESI): m/z 779.6 [M+H] ⁺ . In addition, the aldehyde was recovered during the purification. ¹ H NMR (500 MHz, CDCl ₃ ) δ 9.77 (d, J = 3.3 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.45 (d, J = 7.9 Hz, 2H), 7.35 (s, 1H), 4.74 (q, J = 4.7 Hz, 2H), 4.64 (t, J = 4.6 Hz, 2H), 3.95 (d, J = 3.4 Hz, 2H), 3.88 (d, J = 4.9 Hz, 2H), 3.63 (dt, J = 26.7, 5.8 Hz, 4H), 3.28 (t, J = 4.6 Hz, 2H), 3.17 (d, J = 6.6 Hz, 2H), 1.61 (d, J = 3.7 Hz, 9H), 1.49 (s, 2H), 1.10 (s, 2H). MS (ESI): m/z 597.4 [M+H] ⁺ .

Step 4: A solution of perfluorophenyl 2-((1-((1-(2-(2-azidoethoxy)ethyl)-3-((4-cyanobenzyl)carbamyl)-7-oxo-1,4,5,7-tetrahydro- 6H -pyrazolo[3,4- c ]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoate (36 mg, 0.046 mmol, 1.0 equiv) and _Ph3P (36.4 mg, 0.139 mmol, 3.0 equiv) in toluene (10 mL) was heated to 110 °C for 4 h. The mixture was cooled and concentrated, then the residue was dissolved in 4:1 MeCN/ _H2O (1 mL) and heated at 60 °C for 14 h. The mixture was concentrated and purified by preparative TLC [ _Rf = 0.3, 70% (3:1 EtOAc-EtOH)/heptane]. Silica was stirred in 10% MeOH/DCM, filtered, and concentrated to give semipure material. Further purification by RP-HPLC gave the lactamide macrocyclic N- (4-cyanobenzyl)carboxamide (241). ¹ H NMR (500 MHz, DMSO- d ₆ ) δ 8.94 (t, J = 6.3 Hz, 1H), 7.85 (s, 1H), 7.81-7.75 (m, 2H), 7.52-7.44 (m, 2H), 4.47 (d, J = 6.2 Hz, 2H), 3.75 (t, J = 4.5 Hz, 2H), 3.62-3.58 (m, 6H), 3.24 (s, 2H), 2.96 (t, J = 6.9 Hz, 2H), 1.95-1.70 (m, 6H), 1.24 (s, 2H), 0.99 (s, 2H). MS (ESI): m/z 569.5 [M+H] ⁺ . Example 242 Amine macrocyclic N- (4-cyanobenzyl)formamide (242)

Step 1: A solution of N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (49) (100 mg, 0.206 mmol, 1.0 equiv) and 1-bromo-2-(2-bromoethoxy)ethane (47.8 mg, 0.206 mmol, 1.0 equiv) in DMF (500 _µL ) was treated with _Cs2CO3 (134 mg, 0.412 mmol, 2.0 equiv) at room temperature. After 2 h, NaN ₃ (26.8 mg, 0.412 mmol, 2.0 eq) was added in one portion and the mixture was stirred at room temperature for 30 min, then at 40 °C for 12 h. Additional NaN ₃ (26.8 mg, 0.412 mmol, 2.0 eq) was added and the mixture was heated to 60 °C for 1 h, then diluted with H ₂ O (5 mL) and EtOAc (5 mL). The aqueous phase was extracted with EtOAc (3×5 mL) and the combined organic extracts were dried over Na ₂ SO ₄ , filtered, and concentrated. The residue was purified by column chromatography (SiO ₂ , 0-100%, EtOAc/heptane) to give 1-(2-(2-azidoethoxy)ethyl) -N -(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide. MS (ESI): m/z 599.5 [M+H] ⁺ .

Step 2: 1-(2-(2-azidoethoxy)ethyl) -N- (4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro- 1H -pyrazolo[3,4- c ]pyridine-3-carboxamide (80 mg, 0.134 mmol, 1.0 equiv) and NMO monohydrate (181 mg, 1.34 mmol, 10 equiv) were dissolved in MeCN (700 µL) followed by the addition of TPAP (3.76 mg, 10.69 µmol, 0.08 equiv) at room temperature. After 2 h, additional TPAP (3.76 mg, 10.69 µmol, 0.08 equiv) was added. After stirring for 1 hour, the reaction mixture was quenched with i- PrOH (100 µL) and concentrated. The residue was acidified to pH 3 with 2 M NaHSO ₄ and extracted with Et ₂ O (6 × 5 mL). The combined organic extracts were washed with Na ₂ SO ₄ , dried, filtered, and concentrated to give 2-((1-((1-(2-(2-azidoethoxy)ethyl)-3-((4-cyanobenzyl)carboxamido)-7-oxo-1,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)methyl)cyclopropyl)sulfonyl)-2-methylpropanoic acid and 1-(2-(2-azidoethoxy)ethyl)-N-(4-cyanobenzyl)-6-((1-((2-methyl-1-oxopropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide in a ratio of about 5:1. mixture.

Step 3: A solution of 1-(2-(2-azidoethoxy)ethyl)-N-(4-cyanobenzyl)-6-((1-((2-methyl-1-oxopropan-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (15 mg, 0.025 mmol, 1.0 equiv) obtained from step 241 and _Ph3P (19 mg, 0.075 mmol, 3.0 equiv) in toluene (3 mL) was heated to 110 °C for 16 h. The mixture was cooled to room temperature and _NaBH4 (2.8 mg, 0.075 mmol, 3.0 equiv) was added in one portion. After 10 min, MeOH (100 µL) was added (gas evolution) and the mixture was diluted with H ₂ O (5 mL) and CH ₂ Cl ₂ (5 mL). The aqueous phase was extracted with CH ₂ Cl ₂ (3 × 5 mL) and the combined organic extracts were dried over MgSO ₄ , filtered, and concentrated. The crude material was purified by RP-HPLC to give the amine macrocyclic N -(4-cyanobenzyl)carboxamide (242). ¹ H NMR (500 MHz, MeOH- d ₄ ) δ 8.93 (t, J = 5.2 Hz, 2H), 7.71 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 5.61 (br s, 2 H), 4.63 (d, J = 5.2 Hz, 2H), 3.71-3.87 (m, 6H), 3.42 (s, 2H), 3.14 (br s, 2H), 2.05 (br s, 2H), 1.24-1.77 (d, J = 75.6 Hz, 4H). MS (ESI): m/z 555.7 [M+H] ⁺ . Example 243 N-(4-cyanobenzyl)-6-((1-(N-(6-(hydroxymethyl)pyridin-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (243)

N-(4-cyanobenzyl)-6-((1-(N-(6-(hydroxymethyl)pyridin-2-yl)sulfonamido)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (243) was synthesized using the procedure provided for Example 155 (see also Wang et al., Tet. Lett., pp. 7-10, 53, 2012), with the exception that 2-bromopyridine was replaced by (6-bromo-2-pyridinyl)methanol. Intermediate 155a was obtained using the method described in Example 123, step 4, with the exception that methylamine was replaced by NH ₃ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.93 (t, J = 6.2 Hz, 1H), 8.40 (s, 1H), 8.31 (d, J = 12.4 Hz, 2H), 7.83 - 7.76 (m, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.47 (d, J = 6.2 Hz, 2H), 4.10 (s, 3H), 3.96 (s, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.17 (s, 1H), 2.89 (t, J = 6.8 Hz, 2H), 1.47 (s, 2H), 1.24 (s, 2H), 1.16 (q, J = 5.3 Hz, 2H). 19F NMR (376 MHz, DMSO-d6) δ -74.86. LCMS (ESI): m/z 550.2 [M+H] ⁺ . Example 244 6-((1-(N-(6-acetamidopyridin-2-yl)sulfonamido)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (244)

6-((1-(N-(6-acetamidopyridin-2-yl)sulfonamido)cyclopropyl)methyl)-N-(4-cyanobenzyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (244) was synthesized using the procedure provided for Example 155, except that 2-bromopyridine was replaced with N-(6-aminopyridin-2-yl)acetamide. Intermediate 155a was obtained using the method described in Example 123, step 4, except that methylamine was replaced with NH ₃ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.09 (d, J = 15.8 Hz, 2H), 8.93 (t, J = 6.3 Hz, 1H), 7.83 - 7.70 (m, 3H), 7.67 (t, J = 7.9 Hz, 1H), 7.51 - 7.44 (m, 2H), 6.81 (d, J = 8.0 Hz, 1H), 4.47 (d, J = 6.2 Hz, 2H), 4.12 (s, 3H), 3.96 (s, 2H), 3.62 (t, J = 6.8 Hz, 2H), 2.91 (t, J = 6.8 Hz, 2H), 2.83 (t, J = 6.8 Hz, 0H), 2.11 (s, 3H), 1.49 (q, J = 5.0 Hz, 2H), 1.13 - 1.05 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -75.07. LCMS (ESI): m/z 577.2 [M+H] ⁺ . Example 245 N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyrrolidone-2-yl)sulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (245)

N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-(pyridin-2-yl)sulfonamido)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (245) was synthesized using the procedure provided for Example 155, except that 2-bromopyridine was replaced with 2-bromopyridine. Intermediate (155a) was obtained using the method described in Example 123, step 4, except that methylamine was replaced with NH ₃ . ¹ H NMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.93 (t, J = 6.2 Hz, 1H), 8.40 (s, 1H), 8.31 (d, J = 12.4 Hz, 2H), 7.83 - 7.76 (m, 2H), 7.48 (d, J = 8.2 Hz, 2H), 4.47 (d, J = 6.2 Hz, 2H), 4.10 (s, 3H), 3.96 (s, 2H), 3.63 (t, J = 6.8 Hz, 2H), 3.17 (s, 1H), 2.89 (t, J = 6.8 Hz, 2H), 1.47 (s, 2H), 1.24 (s, 2H), 1.16 (q, J = 5.3 Hz, 2H). 19F NMR (376 MHz, DMSO-d6) δ -74.86. LCMS (ESI): m/z 521.2 [M+H] ⁺ . Example 246 N-(4-Cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-phenylaminosulfonyl)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (246)

N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-(N-phenylsulfonylamino)cyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (246) was synthesized using the procedure provided for Example 155, except that 2-bromopyridine was replaced by bromobenzene. Intermediate (155a) was obtained using the method described in Example 123, step 4, except that methylamine was replaced by NH ₃ . ¹ H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 2H), 8.94 (t, J = 6.3 Hz, 2H), 8.08 - 7.69 (m, 3H), 7.48 (d, J = 8.1 Hz, 2H), 7.42 - 7.18 (m, 4H), 7.13 (t, J = 7.2 Hz, 1H), 4.47 (d, J = 6.1 Hz, 3H), 4.11 (s, 3H), 3.91 (s, 2H), 3.61 (t, J = 6.8 Hz, 4H), 2.94 (t, J = 6.8 Hz, 2H), 1.14 (q, J = 4.9, 4.5 Hz, 2H), 1.10 - 0.89 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -74.76. LCMS (ESI): m/z 519.2 [M+H] ⁺ . Example 247 N-(4-cyanobenzyl)-6-((1-(N-(3-fluoropyridin-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (247)

N-(4-cyanobenzyl)-6-((1-(N-(3-fluoropyridin-2-yl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (247) was synthesized using the procedure provided for Example 155, except that 2-bromopyridine was replaced by 3-fluoropyridin-2-amine. Intermediate (155a) was obtained using the method described in Example 123, step 4, except that methylamine was replaced by NH ₃ . ¹ H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 6.3 Hz, 1H), 7.76 (dd, J = 27.1, 8.7 Hz, 3H), 7.48 (d, J = 8.0 Hz, 2H), 4.47 (d, J = 6.2 Hz, 3H), 4.12 (s, 3H), 4.04 (s, 2H), 3.69 (t, J = 6.8 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H), 1.42 (s, 2H), 1.13 (s, 2H). 19F NMR (376 MHz, DMSO-d6) δ -75.17. LCMS (ESI): m/z 538.2 [M+H] ⁺ . Example 248 N-(4-cyanobenzyl)-6-((1-(N-(2-cyanophenyl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (248)

N-(4-cyanobenzyl)-6-((1-(N-(2-cyanophenyl)sulfonylamine)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (248) was synthesized using the procedure provided for Example 155, except that 2-bromopyridine was replaced by bromobenzene. Intermediate (155a) was obtained using the method described in Example 123, step 4, except that methylamine was replaced by NH ₃ . ¹ H NMR (400 MHz, methanol-d4) δ 8.16 (dd, J = 7.5, 1.8 Hz, 1H), 7.82 - 7.61 (m, 2H), 7.61 - 7.41 (m, 2H), 4.62 (s, 2H), 4.26 - 4.14 (m, 1H), 4.13 - 4.02 (m, 3H), 3.87 (t, J = 6.8 Hz, 2H), 3.11 (q, J = 7.1 Hz, 2H), 1.54 (s, 2H), 1.31 (s, 2H), 1.27 - 1.10 (m, 2H). 19F NMR (376 MHz, methanol-d4) δ -77.96. LCMS (ESI): m/z 545.2 [M+H] ⁺ . Examples 249-251 N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (249) was synthesized using the procedure provided for Example 189, with the exception that (4-chlorophenyl)-methylamine was replaced with (4-chloro-3-fluorophenyl)-methylamine. Enantiomers (250, 251) were obtained by chiral SFC separation as described in Examples 190 and 191. N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (249): 1H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 6.3 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.31 (dd, J = 10.4, 2.0 Hz, 1H), 7.16 (dd, J = 8.3, 1.9 Hz, 1H), 4.39 (d, J = 6.2 Hz, 2H), 4.19 - 4.03 (m, 5H), 3.86 (dd, J = 7.1, 3.4 Hz, 1H), 3.70 - 3.53 (m, 3H), 3.36 (dd, J = 11.4, 7.1 Hz, 1H), 2.98 (t, J = 6.8 Hz, 2H), 2.48 (s, 5H), 1.50 - 1.24 (m, 8H), 1.07 - 0.96 (m, 2H), 0.96 - 0.92 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -75.61 (d, J = 83.6 Hz), -116.87 - -117.83 (m). LCMS (ESI): m/z 557.2 [M+H] ^{+ .}

( R )-N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (250): 1H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 6.3 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.31 (dd, J = 10.4, 2.0 Hz, 1H), 7.16 (dd, J = 8.3, 1.9 Hz, 1H), 4.39 (d, J = 6.2 Hz, 2H), 4.19 - 4.03 (m, 5H), 3.86 (dd, J = 7.1, 3.4 Hz, 1H), 3.70 - 3.53 (m, 3H), 3.36 (dd, J = 11.4, 7.1 Hz, 1H), 2.98 (t, J = 6.8 Hz, 2H), 2.48 (s, 5H), 1.50 - 1.24 (m, 8H), 1.07 - 0.96 (m, 2H), 0.96 - 0.92 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -75.61 (d, J = 83.6 Hz), -116.87 - -117.83 (m). LCMS (ESI): m/z 557.2 [M+H] ⁺ . SFC: Rt = 4.87 min, 99% ee.

( S )-N-(4-chloro-3-fluorobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (251). ¹ H NMR (400 MHz, DMSO-d6) δ 8.93 (t, J = 6.3 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.31 (dd, J = 10.4, 2.0 Hz, 1H), 7.16 (dd, J = 8.3, 1.9 Hz, 1H), 4.39 (d, J = 6.2 Hz, 2H), 4.19 - 4.03 (m, 5H), 3.86 (dd, J = 7.1, 3.4 Hz, 1H), 3.70 - 3.53 (m, 3H), 3.36 (dd, J = 11.4, 7.1 Hz, 1H), 2.98 (t, J = 6.8 Hz, 2H), 2.48 (s, 5H), 1.50 - 1.24 (m, 8H), 1.07 - 0.96 (m, 2H), 0.96 - 0.92 (m, 1H). 19F NMR (376 MHz, DMSO-d6) δ -75.61 (d, J = 83.6 Hz), -116.87 - -117.83 (m). LCMS (ESI): m/z 557.2 [M+H] ⁺ . SFC: Rt = 6.47 min, 99% ee. Example 252 N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

N-(4-Cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (252) was synthesized using the procedure provided for Example 189 with the exception that (4-chlorophenyl)methanamine was replaced with 4-(aminomethyl)benzonitrile. Enantiomers (192) and (193) were obtained by chiral SFC separation as described in Examples 190 and 191.

N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (252): 1H NMR (400 MHz, DMSO-d6) δ 8.98 (t, J = 6.3 Hz, 1H), 7.83 - 7.76 (m, 2H), 7.51 - 7.44 (m, 2H), 4.47 (d, J = 6.3 Hz, 2H), 4.19 - 4.00 (m, 5H), 3.86 (dd, J = 7.1, 3.4 Hz, 1H), 3.70 - 3.53 (m, 3H), 3.36 (dd, J = 11.4, 7.1 Hz, 1H), 2.97 (t, J = 6.8 Hz, 2H), 1.42 (s, 3H), 1.31 (d, J = 18.3 Hz, 5H), 1.08 - 0.92 (m, 2H). 19F NMR (376 MHz, DMSO-d6) δ -75.33, -83.92, -84.58. LCMS (ESI): m/z 530.1 [M+H] ^{+ .}

(S)-N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutan-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (192): 19F NMR (376 MHz, DMSO-d6) δ -75.33, -83.92, -84.58.

(R)-N-(4-cyanobenzyl)-6-((1-((3,4-dihydroxy-2-methylbutane-2-yl)sulfonyl)cyclopropyl)methyl)-1-methyl-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (193): 19F NMR (376 MHz, DMSO-d6) δ -75.33, -83.92, -84.58. Example 262 N-(4-cyanobenzyl)-1-methyl-7-oxo-6-((1-aminosulfonylcyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide

N-(4-Cyanobenzyl)-1-methyl-7-oxo-6-((1-aminosulfonylcyclopropyl)methyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (262) was synthesized using the procedure provided for Example 129, except that NH ₃ was replaced by the corresponding amine. ¹ H NMR (400 MHz, DMSO-d6) δ 8.94 (t, J = 6.3 Hz, 1H), 7.87 - 7.68 (m, 2H), 7.48 (d, J = 8.2 Hz, 2H), 6.91 (s, 2H), 4.47 (d, J = 6.2 Hz, 2H), 4.12 (s, 2H), 3.94 (s, 2H), 3.68 (t, J = 6.8 Hz, 2H), 2.98 (t, J = 6.8 Hz, 2H), 1.20 (dd, J = 6.8, 4.5 Hz, 2H), 1.14 - 0.89 (m, 2H). LCMS (ESI): m/z 443.2 [M+H] ^{+ .}

The compounds of the present invention can also be used as intermediates in the synthesis of other compounds within the scope of the present invention. As an example, refer to Example 155, in which Example 262 of the present invention serves as an intermediate (labeled as 155a) for the final product Example 155. The biological activity of the compounds of the present invention was determined using the following method. CMV and HSV polymerase protein production

Both human CMV DNA polymerase UL54 and human HSV DNA polymerase UL30 were produced as N-terminal MBP fusions of the full-length wild-type recombinant proteins to enhance soluble expression in an insect cell expression system. Proteins were expressed in sf9 insect cells via bacillivirus transduction and cells were harvested 48 hours later. Soluble proteins were purified via an N-terminal hexahistidine tag followed by heparin affinity chromatography using a standard Ni-IMAC purification strategy. Both final MBP fusion proteins were more than 90% pure with yields of up to 1.8 mg per liter of culture for UL54 and up to 15 mg per liter of culture for UL30. All purification steps were performed on ice with buffers cooled on ice and FPLC fraction collector set at 6°C. Final UL54 protein was concentrated and stored at -20°C in buffer containing 35 mM Tris pH 7.5, 375 mM NaCl, 42.5% glycerol, and 1 mM TCEP. UL30 protein was stored at -80°C in buffer containing 20 mM HEPES pH 7.0, 420 mM NaCl, 20% glycerol, 6 mM imidazole, and 0.8 mM DTT. CMV and HSV polymerase biochemical analysis

DNA polymerase activity was measured using a molecular beacon-based assay (as described in Ma et al.) 100 pM CMV polymerase or 625 pM HSV polymerase was added to a buffer containing 20 mM Tris pH=7.5, 100 mM NaCl, 10 mM MgCl ₂ , 0.01% Tween-20, 0.5 mM EDTA, 10% sucrose, and 1 mM DTT. Inhibitors were pre-incubated with the polymerase at room temperature for 30 minutes. Reactions were initiated by adding a mixture containing: 1.25 uM dATP, 1.25 uM dCTP, 1.25 uM dTTP, 1.25 uM dGTP, 200 nM Primer B (5'-GAC GGG AAG-3'5'-GAC GGG AAG-3') and 100 nM Molecular Beacon (5'-5,6-FAM-CCT CTC CGT GTC TTG TAC TTC CCG TCA GAG AGG-BHQ1-3'). For human CMV polymerase, the reactions were incubated at room temperature for 60 minutes. For HSV polymerase, the reactions were incubated at room temperature for 20 minutes. The reactions were then read on a Perkin-Elmer EnVision 2101 reader (fluorescence) using 480 nm excitation and 535 nm emission. IC50 was determined using in-house Novartis software (Helios). Reference: Ma et al. (2006). Real-time monitoring of DNA polymerase activity using molecular beacon. Analytical Biochemistry , 353 (1): 141-143 CMV polymerase and HSV polymerase assay protocols

100 pM CMV polymerase or 625 pM HSV polymerase was added to a buffer containing 20 mM Tris pH=7.5, 100 mM NaCl, 10 mM MgCl2, 0.01% Tween-20, 0.5 mM EDTA, 10% sucrose, and 1 mM DTT. The inhibitor was pre-incubated with the polymerase at room temperature for 30 minutes. Reactions were initiated by adding a mixture containing: 1.25 uM dATP, 1.25 uM dCTP, 1.25 uM dTTP, 1.25 uM dGTP, 200 nM Primer B (5'-GAC GGG AAG-3'5'-GAC GGG AAG-3') and 100 nM Molecular Beacon (5'-5,6-FAM-CCT CTC CGT GTC TTG TAC TTC CCG TCA GAG AGG-BHQ1-3'). For human CMV polymerase, the reactions were incubated at room temperature for 60 minutes. For HSV polymerase, the reactions were incubated at room temperature for 20 minutes. The reactions were then read on a Perkin-Elmer EnVision 2101 reader (fluorescence) using 480 nm excitation and 535 nm emission. Cellular Herpes Virus Replication Assay Compound Dilution:

For all viral assays, 10 mM DMSO stock compound solutions were serially diluted in 3.16-fold dilutions in DMSO in 96-well clear round-bottom plates. Compounds were then diluted 1:20 in assay medium and 10 µL of these dilutions were subsequently added to cells to achieve final compound concentrations ranging from 0.0159 µM to 50 µM in 0.5% DMSO/assay medium or 0.00318 to 10 µM in 0.5% DMSO/assay medium. CMV Luciferase Assay:

The assay uses HCMV encoding luciferase. Luciferase is expressed in the AD169 strain under the control of the late viral gene (pp28) promoter, so reporter gene expression is dependent on viral DNA replication. Compounds that affect viral entry into any stage of DNA replication cause changes in luciferase levels.

For compound 1-242, viral replication in the presence or absence of compound was measured by luciferase activity according to the following procedure: Neonatal normal human dermal fibroblasts (NN-NHDF, obtained from ATCC catalog #201-010) were seeded at 9,000 cells/well in 96-well white solid bottom plates in 80 μl/well of assay medium, DMEM/high glucose/glutamine-free/phenol red-free medium (Invitrogen catalog #31053) containing 2% FBS, 4 mM GlutaMax® (Invitrogen catalog #35050). After 2 hours at 37°C, 10 uL of compound diluted in assay medium or 5% DMSO (final 0.5% DMSO/well) was added and the plates were allowed to return to 37°C. One hour later, 10 uL of virus diluted in assay medium was added at a final multiplicity of infection (MOI) of 1. The plates were incubated at 37°C for 72 hours. At 72 hours post infection (hpi), the plates were equilibrated to room temperature. After 25 minutes, 100 uL of Renilla-Glo® Luciferase Assay Reagent (Promega Catalog # E2750) was added to each well and incubated for 10 minutes. The plates were covered to protect from light. Luminescence was measured on a PHERAstar FS®.

The following controls were included in the data analysis: no virus, no compound (0.5% DMSO) = IC (maximum inhibition control); virus, no compound (0.5% DMSO) = NC (neutral control). Data were analyzed using in-house Novartis software (Helios). Results were normalized to % scale using the mean of the control groups (NC, IC) using the following formula: % control = 100 - (100×(sample value - NC)/(IC-NC)).

For each compound, the software used a 4-parameter logic model to derive EC ₅₀ . CMV luciferase assay for compounds 243-262

Compounds 243-262 were tested in the luminescence assay as follows.

ARPE-19 cells were maintained in growth medium (DMEM/F12 Glutamax + 10% fetal bovine serum (FBS) + Penicillin-Strep) and, before reaching full confluence, transferred to centrifuge tubes and spun at 1000 rpm for 5 minutes. Cells were resuspended in assay medium (DMEM/F12 Glutamax + 2% FBS + Penicillin-Strep) and counted. Cell density was adjusted to one million cells/ml and infected with HCMV-Rluc virus (AD169 pp28-hRluc rUL131; MOI 0.6) for 2 hours in 50 ml conical tubes while shaking. After diluting the infection suspension tenfold (to 100,000 cells/ml), 8000 cells were plated directly into 384-well plates pre-spotted with the compound to be tested. Cells were incubated at 37°C for 72 hours. The cells were then placed at room temperature and allowed to equilibrate for 20 minutes before adding Renilla-Glo (Promega) reagent. After incubation for 10 minutes at room temperature, luminescence was measured on a microplate reader.

HSV-1 qPCR Assay: The assay uses the KOS strain of HSV-1 virus (ATCC catalog number VR-1493). Viral replication in the presence or absence of compound was measured by qPCR according to the following procedure: NN-NHDF cells were seeded at 9,000 cells/well in 80 μL/well assay medium (same as CMV) in 96-well white-walled clear-bottom culture plates and placed in a laminar flow hood at room temperature for 20 minutes, followed by incubation at 37°C. One hour later, 10 μL of diluted compound or 10 μL of 5% DMSO as a control was added to each well (final 0.5% DMSO). One hour later, virus was added in 10 μL/well assay medium at a final MOI of 0.01. Cells were then incubated at 37°C. After 24 hours, the medium was removed, the cells were washed once with 100 µL DPBS (Invitrogen, Catalog No. 21-031-CV), and lysed using the prepGEM® Tissue Kit (ZyGEM, Catalog No. PTI0500K) by adding 100 µL prepGEM® Master Mix (89 µL H ₂ O, 10 µL 10x prepGEM® Buffer, 1 µL prepGEM® Enzyme/well) to each well. The plate was sealed with an aluminum foil seal and lysed on a 75°C heating block for 15 minutes. The plate was then allowed to cool to room temperature with gentle shaking before being transferred to the qPCR apparatus.

VZV qPCR Assay: The assay utilizes co-infection of MRC-5 cells infected with the VZV Ellen strain (ATCC Catalog No. VR-1367). Viral replication in the presence or absence of compound was measured by qPCR according to the following procedure: 12,000 uninfected MRC-5 cells were mixed with VZV-infected MRC-5 cells at a ratio of 1 to 10 infected cells to uninfected cells in 90 μl/well of assay medium (EMEM (ATCC Catalog No. 30-2003) containing 4% FBS) in a 96-well white-walled clear-bottom plate. After 1 hour at 37°C, 10 μL of diluted compound or 10 μL of 5% DMSO as a control was added to each well (final 0.5% DMSO). The cells were then incubated at 37°C. At 6 h after co-culture, the selected ratio of infected cells to uninfected cells yielded approximately 3% VZV-positive cells as detected by immunofluorescence staining for the VZV immediate early 62 gene. Two days later, the medium was removed, and the cells were washed once with 100 µL DPBS and lysed using the prepGEM tissue kit as described above.

EBV qPCR Assay: The assay uses the SNU-719 gastric cancer cell line latently infected with EBV. After reactivation with chemical reagents, the number of EBV DNA copies is measured by qPCR. Viral replication in the presence or absence of compound is measured according to the following procedure: SNU-719 cells are seeded at 2×10 ⁴ cells/well in 96-well clear bottom black culture plates in 80 μl/well of assay medium (RPMI 1640 (ATCC Catalog No. 30-2001) containing 2% FBS). After 1 hour at 37°C, 10 μL of diluted compound or 10 μL of 5% DMSO as a control is added to each well (final 0.5% DMSO). Lytic replication of the virus was then activated by adding 10 μL of a mixture of 20 ng/ml tetradecylphorbol acetate (TPA) and 3 mM sodium butyrate (NaB). At 18 hpi, the medium was removed, fresh assay medium with compound or DMSO was added, and the cells were allowed to return to 37°C. After 72 hours of lytic replication, the medium was removed, the cells were washed with 100 μL DPBS and lysed using the prepGEM tissue kit as described previously. qPCR procedures and data analysis for HSV , VZV , and EBV :

qPCR reactions were performed in a total reaction volume of 20 µL using the QuantiFast® Multiplex PCR Kit (Qiagen Catalog No. 204656). 18 µL of qPCR Master Mix (10 µL of 2x QuantiFast® Multiplex PCR Master Mix, 1 µL of 20x Primer/Probe Mix specific for housekeeping genes, 1 µL of 20x Primer/Probe Mix specific for viral genes, 6 µL of H ₂ O) was dispensed into each well of a 384-well plate. 2 µL of cell lysate was added to each well. Each cell lysate was run in duplicate. The plates were sealed with clear seals, briefly centrifuged, and qPCR reactions were performed in an ABI 7900HT instrument using the following conditions: 95°C for 5 min, followed by 40 cycles of 95°C for 30 sec, 60°C for 30 sec.

Relative quantification was calculated using the ΔΔC _T method and then converted to percent inhibition. Calibration values were determined using virus + DMSO samples (drug-free). EC ₅₀ values were calculated using the XLFit dose-response single-site model 205. qPCR primers and probes Primer/probe specificity Sequence (5'-3') HSV-1 qPCR: HSV-1 gpJ gene, forward primer TAGTCGGTGGGCTGTGT (SEQ ID NO:1) HSV-1 gpJ gene, reverse primer AACTGGGTCCATGTAGGGAT (SEQ ID NO:2) HSV-1 gpJ gene, probe TGCTTGAGCTCCTGCGTCGTAC (SEQ ID NO:3) VZV qPCR: VZV IE62 gene, forward primer CCTCCGTATCGGGACTTCAA (SEQ ID NO:4) VZV IE62 gene, reverse primer TGACCGTCCTCGCATACGTA (SEQ ID NO:5) VZV IE62 gene, probe TTTGGCGAAGAGCTAAC (SEQ ID NO:6) Housekeeping genes for HSV and VZV analysis: Forward MT-ATP6 primer ACACCCCTTATCCCCATACTAG (SEQ ID NO:7) Reverse MT-ATP6 primer ATGGTTGATATTGCTAGGGTGG (SEQ ID NO:8) MT-ATP6 probe ACCGCTAACATTACTGCAGGCCA (SEQ ID NO:9) EBV qPCR: EBV BNRF1 forward primer CGGCCGTGATGGAGGCTATG (SEQ ID NO:10) EBV BNRF1 reverse primer AGACAGAGGCCACCACGG (SEQ ID NO:11) EBV BNRF1 probe TGACCTTTGGCTCGGCCTCCTGC (SEQ ID NO:12) Housekeeping genes for EBV analysis: HuALB forward primer GCTGTCATCTCTTGTGGGCTGT (SEQ ID NO:13) HuALB reverse primer AAACTCATGGGAGCTGCTGGTT (SEQ ID NO:14) HuALB Probe CCTGTCATGCCCACACAAATCTCTCC (SEQ ID NO:15) Table 17: Biological activity data Instance Number CMV-Polymerase Biochemical IC ₅₀ (uM) CMV-Luc Cell EC ₅₀ (uM) HSV-Polymerase Biochemical IC ₅₀ (uM) 1 0.010 0.124 0.269 2 0.027 0.536 1.876 3 0.002 0.039 0.055 4 0.002 0.023 0.048 5 0.030 0.284 0.416 6 0.030 0.770 0.959 7 0.056 0.534 0.861 8 0.035 0.339 1.632 9 0.001 0.031 0.045 10 0.026 0.259 0.641 11 0.017 0.214 2.229 12 0.002 0.087 0.346 13 0.006 0.102 0.311 14 0.095 0.585 1.611 15 0.011 0.162 0.385 16 0.013 0.170 0.239 17 16.924 >10 >25 18 0.022 0.301 1.055 19 0.055 >10 8.183 20 0.006 0.106 0.259 twenty one 0.009 0.147 0.517 twenty two 0.012 0.113 0.436 twenty three 0.007 0.086 0.345 twenty four 0.018 0.197 0.467 25 0.002 0.030 0.053 26 0.052 0.761 3.956 27 0.007 0.211 nd 28 0.001 0.024 0.029 29 0.001 0.080 0.086 30 0.940 >10 6.238 31 0.012 0.101 0.293 32 0.003 0.041 0.161 33 1.185 9.935 >25 34 0.001 0.010 0.010 35 0.003 0.038 0.141 36 0.005 0.571 nd 37 0.007 0.105 nd 38 0.014 0.607 0.784 39 0.025 0.376 0.625 41 9.770 >10 nd 42 0.149 1.184 1.999 43 0.002 0.066 0.101 44 0.004 0.076 0.137 45 0.006 0.146 0.169 46 0.041 0.746 1.777 47 0.002 0.042 0.059 48 0.011 0.331 0.801 49 0.004 0.058 0.037 50 0.001 0.020 0.016 51 0.006 0.172 0.089 52 0.001 0.019 0.019 53 0.007 0.141 0.070 54 0.002 0.053 0.103 55 0.601 >10 >25 56 0.001 0.021 0.017 57 0.001 0.022 0.035 58 0.001 0.025 0.024 59 0.001 0.033 0.023 60 0.002 0.062 0.045 61 0.006 0.145 0.075 62 0.004 0.136 0.139 63 0.006 0.220 0.100 64 0.004 0.106 0.060 65 0.002 0.050 0.052 66 0.002 0.088 0.050 67 0.002 0.082 0.048 68 0.001 0.115 0.021 69 0.001 0.057 0.040 70 0.003 0.061 0.037 71 0.001 0.095 0.033 72 0.002 0.083 0.051 73 0.002 0.053 0.040 74 0.003 0.148 0.065 75 0.007 0.047 0.133 76 0.010 0.084 0.123 77 0.012 0.115 0.142 78 0.026 0.112 0.206 80 0.006 0.036 0.067 81 0.003 0.042 0.046 82 0.002 0.029 0.082 83 0.001 0.133 0.071 84 0.004 0.051 0.045 85 0.003 0.050 0.049 86 0.018 0.145 0.159 87 0.001 0.044 0.032 88 0.002 0.036 0.039 90 0.007 0.058 0.097 91 0.005 0.076 0.069 92 0.001 0.012 0.030 93 0.001 0.005 0.025 94 0.009 0.022 0.054 95 0.002 0.011 0.025 96 0.001 0.026 0.020 97 0.001 0.008 0.023 98 0.001 0.008 0.026 99 0.004 0.014 0.063 100 0.004 0.013 0.060 101 0.001 0.009 0.032 102 0.005 0.026 0.042 103 0.009 0.041 0.117 104 0.003 0.021 0.108 105 0.001 0.042 0.032 107 0.872 >10 >25 108 0.001 0.032 0.047 109 0.003 0.078 0.076 110 0.005 0.218 0.166 111 0.005 0.159 0.148 112 0.002 0.064 0.089 113 0.003 0.036 0.038 115 0.003 0.059 0.071 116 0.002 0.039 0.048 117 0.004 0.035 0.059 118 0.019 0.327 0.412 119 0.004 0.156 0.153 120 0.003 0.151 0.091 121 0.008 0.156 0.671 122 0.007 0.298 0.324 123 0.009 0.157 0.196 124 0.006 0.156 0.121 125 0.003 0.196 0.136 126 0.004 0.118 0.084 127 0.004 0.122 0.067 128 0.005 0.094 0.137 129 0.016 0.247 0.213 130 0.007 0.163 0.122 131 0.016 0.223 0.162 132 0.020 0.289 0.451 133 0.020 0.097 0.258 134 0.031 0.443 0.282 135 0.062 0.536 1.086 136 0.018 0.199 0.243 137 0.044 0.636 0.691 138 0.021 0.127 0.326 139 0.008 0.533 0.143 140 0.011 0.418 0.147 141 0.013 0.051 0.192 142 0.018 0.066 0.268 143 0.019 0.138 0.344 144 0.004 0.044 0.067 145 0.014 0.303 0.237 146 0.003 0.061 0.074 147 0.030 0.604 0.644 148 0.015 0.139 0.155 149 0.012 0.166 0.161 150 0.006 0.067 0.081 151 0.008 0.064 0.118 152 0.030 0.834 0.827 153 0.020 0.305 0.292 154 0.002 0.083 0.038 155 0.002 0.057 0.078 156 0.003 0.100 0.062 157 0.002 0.058 0.046 158 0.003 0.037 0.058 159 0.013 0.298 0.423 160 0.006 0.118 0.301 161 0.002 0.061 0.040 162 0.001 0.030 0.018 163 0.002 0.067 0.036 164 0.006 0.157 0.185 165 0.001 0.136 0.014 166 0.001 0.088 0.012 167 0.004 0.517 0.104 168 0.004 0.072 0.097 169 0.014 0.201 0.238 170 0.004 0.124 0.122 171 0.003 0.104 0.078 172 0.005 0.069 0.063 173 0.003 0.074 0.062 174 0.006 0.212 0.092 175 0.003 0.026 0.027 176 0.002 0.052 0.039 177 0.004 0.168 0.122 178 0.240 9.723 8.059 179 0.002 0.049 0.061 181 0.004 0.077 0.069 182 0.002 0.050 0.046 183 0.005 0.220 0.065 184 0.004 0.165 0.052 185 0.004 0.275 0.059 186 0.008 0.090 0.037 187 0.013 0.071 0.086 188 0.022 0.160 0.108 190 0.001 0.019 0.020 191 0.001 0.005 0.011 192 0.001 0.035 0.030 193 0.001 0.022 0.011 194 0.001 0.050 0.020 195 0.001 0.053 0.023 196 0.001 0.019 0.019 197 0.001 0.020 0.019 198 0.001 0.018 0.023 199 0.001 0.019 0.028 200 0.001 0.005 0.014 201 0.001 0.006 0.015 202 0.002 0.030 0.030 203 0.002 0.019 0.038 204 0.003 0.011 0.037 205 0.002 0.009 0.029 206 0.021 0.071 0.074 207 0.023 0.050 0.088 208 0.001 0.051 0.022 209 0.001 0.010 0.016 211 0.009 0.028 0.077 212 0.003 0.007 0.039 213 0.002 0.081 0.048 214 0.003 0.042 0.032 215 0.001 1.900 0.028 216 0.002 0.067 0.069 217 0.001 0.029 0.026 218 0.006 0.042 0.050 219 0.030 0.207 0.401 220 0.001 0.049 0.023 221 0.001 0.017 0.013 222 0.003 0.033 0.043 223 0.005 0.049 0.035 225 0.004 0.063 0.090 226 0.002 0.044 0.101 227 0.001 0.028 0.031 228 0.002 0.051 0.056 229 0.001 0.020 0.031 230 0.001 0.031 0.034 231 0.007 0.088 0.278 232 0.006 0.160 0.339 233 0.002 0.096 0.150 234 0.001 0.049 0.019 235 0.001 0.031 0.016 236 0.004 0.077 0.091 237 0.002 0.038 0.041 238 0.001 0.016 0.016 239 0.001 0.023 0.020 240 0.001 0.043 0.034 241 0.013 0.467 0.393 242 0.006 0.101 0.319 Note: nd indicates not determined Table 18: Cellular activity against various human herpes viruses (EC ₅₀ , μM) Instance Number CMV HSV-1 V Z EBV 3 0.039 0.033 0.011 nd 4 0.023 0.064 0.008 nd 92 0.012 0.03 nd nd 175 0.026 0.058 0.034 0.008 176 0.052 0.095 0.074 0.014 193 0.026 0.058 0.034 0.008 198 0.022 0.05 0.039 0.004 199 0.018 0.03 0.127 0.011 200 0.005 0.016 nd nd 201 0.006 0.018 nd nd 216 0.067 0.112 0.109 0.028 217 0.029 0.036 nd nd 221 0.017 0.01 nd nd 234 0.049 0.083 0.115 0.011 Note: nd indicates not determined Table 19: Biological Activity Data Instance Number CMV-Luc EC ₅₀ in ARPE-19 cells (nM) 243 115.42 244 116.31 245 181.13 246 74.461 247 387.64 248 10000 249 8.244 250 26.72 251 9.83 252 21.86 253 386.03 254 1000 255 312.51 256 10000 257 357.64 258 687.79 259 713.61 260 277.87 261 2576 262 251.82

<110> Novartis AG (Switzerland) Gilead Sciences, Inc. (USA)

<120> Antiviral pyrazolopyridone compounds

<140> TW 109133165

<141> 2020-09-24

<150> US 62/906,664

<151> 2019-09-26

<160> 16

<170> PatentIn version 3.5

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<212> DNA

<213> Artificial sequence

<220>

<223> PCR primers or probes

<400> 14

<210> 15

<211> 26

<212> DNA

<213> Artificial sequence

<220>

<223> PCR primers or probes

<400> 15

<210> 16

<211> 33

<212> DNA

<213> Artificial sequence

<220>

<223> PCR primers or probes

<400> 16

Claims (40)

A compound of formula (I) or a pharmaceutically acceptable salt thereof,

Where: X is

,

,

, a 5-6 membered heteroaryl group having 1 to 4 heteroatoms independently selected from N, O and S as ring members, a 5-6 membered heterocycloalkyl group having 1 to 4 ring members independently selected from N, NH, NR ¹⁷ , O or S, or a 5-6 membered heterocyclic group having 1 to 4 ring members independently selected from N, NH, NR ¹⁷ , O or S; Y is a bond,

,

-O- or

, wherein the * of Y indicates the point of attachment to X and the ** of Y indicates the point of attachment to ^RB ; q is 0 or 1; when q is 1, _LMC is *-((CR ¹¹ R ¹² ) _n O) _m (CR ¹¹ R ¹² ) _p -**, *-C(═O)NR ¹⁵ ((CR ¹¹ R ¹² ) _n O) _m (CR ¹¹ R ¹² ) _p -**, *-(CR 11 R 12 ) _n NR ¹⁵ ((CR ¹¹ R ¹² ) _n O) _m (CR ¹¹ R ¹² ) _p -**, *-(CR ¹¹ R ¹² ) _n NR 15 ((CR ¹¹ R ¹² ) n O) m (CR 11 R 12 ) p -**, *-(CR ¹¹ R ¹² ) _n NR ¹⁵ ) _m (CR ¹¹ R ¹² ) _p -**, *-(CR ¹¹ R ¹² ) C(═O)NR ¹⁵ (CR ¹¹ R ¹² ) _n -**, *-C(=O)NR ¹⁵ (CR ¹¹ R ¹² ) _n -**, *-O(CR ¹¹ R ¹² ) _n -**, or *-NR ¹⁵ (CR ¹¹ R ¹² ) _n -**, wherein the * of L _MC indicates the point of attachment to Z and the ** of L _MC indicates the point of attachment to A; when q is 1, L _MC exists, A is a bond and Z is

or

, wherein * of Z indicates the point of attachment to L _MC and ** of Z indicates the point of attachment to L; m is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; each n is independently selected from 1, 2, 3, 4, 5, 7, 8, 9 and 10; p is 1, 2, 3, 4, 5 or 6; when q is 0, L _MC is absent, and Z is W, and A is R ⁴ ; ^RB is phenyl, pyridyl, thienyl, pyrimidinyl or 5-8 membered cycloalkyl, wherein ^RB is optionally substituted with 1 to 3 R ⁵ groups; R ¹ is selected from H, C _1- C ₃ alkyl and C _1- C ₃ alkyl substituted with 1 to 3 -OH groups; R ² is selected from H, C _1- C ₃ alkyl and C _1- C ₃ alkyl substituted with 1 to 3 -OH groups; or R ¹ and R wherein ^{R 2} together with the carbon to which it is attached can form a 3-6 membered cycloalkyl ring; t is 0, 1 or 2; each R ^3, when present, is a substituent on the ring to which -LW is directly attached, wherein each R ³ is independently selected from halogen, CN, C _1- C ₃ alkoxy, C _1- C ₃ alkyl, C(=O)OR ¹⁰ and C(=O)NR ¹³ R ¹⁴ ; R ⁴ is H, C _1- C ₃ alkyl, C _3- C ₆ cycloalkyl, -(CH ₂ ) ₂ O(CH ₂ ) ₂ Br or C _1- C ₃ alkyl substituted with 1 to 2 groups independently selected from -OH, -C(=O)R ¹⁵ and R ¹⁰ ; each R ⁵ is independently selected from halogen, -CN, hydroxyl, -NR ¹³ R ¹⁴ , C _3- C ₆ cycloalkyl, C _1- C ₃ alkoxy, C _1- C ₃ halogenalkyl and C ₁ -C ₃ alkyl optionally substituted with 1 to 3 R ⁶ groups, wherein when R ^B is substituted with two R ⁵ and each R ⁵ is C _1- C ₃ alkyl optionally substituted with 1 to 3 R ⁶ groups, when directly attached to the same carbon atom, together with the carbon to which the two are directly attached, they can form a 3-5 membered cycloalkyl ring optionally substituted with 1 to 3 R ⁶ groups; each R ⁶ is independently selected from halogen, hydroxy, CN, C _1- C ₃ alkoxy, C _1- C ₃ alkyl and C _3- C ₅ cycloalkyl at each occurrence, or two R The ^6- membered group together with the two directly attached carbon atoms can form a 3-5 membered cycloalkyl ring or a 4-6 membered heterocyclic ring containing O, N or S as a ring member and optionally substituted by 1 to 2 groups independently selected from a pendoxy group and a C _1- C ₃ alkyl group; L is a C ₁ -C ₄ straight chain or branched chain alkyl linking group; W is a 3-6 membered cycloalkyl group, wherein the 3-6 membered cycloalkyl group of W is optionally substituted by 1 to 3 groups independently selected from the following: -SO ₂ R ¹⁰ , -SO ₂ NR ¹⁴ R ¹⁰ , -SO ₂ NR ¹³ R ¹⁴ and -SO ₂ N═CR ¹³ NR ¹³ R ¹⁴ ; R ¹⁰ is selected from C _1- C ₅ alkyl, C _1- C _R 14 , -C 1 -C 4 alkyl, deuterium, C 1 -C 4 halogen, -OH, -CN, -OC(═O)R 14 , -halogen, -C 1 -C 3 alkoxy, -OC(═O)NR ¹³ R ¹⁴ , -C ₁ -C ₄ alkyl, ^-C ₁ -C ₄ halogen, -OH, -CN, -OC(═O)R ^{14 ,} -C ₁ -C ₄ alkyl ^... -SO ₂ R ¹³ , -SO ₂ NR ¹³ R ¹⁴ , -SO ₂ NR ¹³ C(=O)R ¹³ , -C(=O)NR ¹³ SO ₂ R ¹³ , -S(=O)R ¹³ , -S(=O)(=NR ¹⁴ )R ¹³ , -NR ¹³ SO ₂ NR ¹³ R ¹⁴ , -NR ¹³ SO ₂ R ¹³ , -NR ¹³ R ¹⁴ , -NR ¹⁴ C(=O)R ¹³ , -NR ¹⁴ C(=O)OR ¹³ , -C(=O)NR ¹³ R ¹⁴ , -C(=O)OR ¹³ , (containing 1 to 2 independently selected from N, NH, NR ¹⁷ , O or S as ring members), (a 4-7 membered heterocycloalkyl group containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S), C _{3 -} C ₅ cycloalkyl group and (a 5-6 membered heteroaryl ring having 1 to 4 heteroatoms including 1 to 4 nitrogen atoms, 0 or 1 oxygen atoms and 0 or 1 sulfur atoms as ring members), wherein the C _{1 -} C ₄ alkyl group, the 4-7 membered heterocycloalkyl group, the 4-7 membered heterocycloalkyl group, the C _{3 -} C ₅ cycloalkyl group and the 5-6 membered heteroaryl ring are each optionally further substituted with 1 to 3 groups independently selected from the following: halogen group, C _{1 -} C ₃ alkyl group, C _{1 -} C ₃ halogen group, OR ¹³ , CN and NR ¹³ R ¹⁴ ; R ¹¹ and R ¹² are each independently selected from H and C _1- C ₄ alkyl; each R ¹³ is independently selected from H, C _1- C ₄ alkyl, a 4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, a 4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, and a C _3- C ₆ cycloalkyl, wherein the C _1- C ₄ alkyl, the 4-7 membered heterocycloalkyl, the 4-7 membered heterocycloalkyl and the C _3- C ₆ cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C _1- C ₄ alkyl, halogen, -OH, -NR 17 , ^{R 15} R ¹⁶ , -C(=O)OR ¹⁵ , C _1- C ₂ alkoxy and C _1- C ₄ alkyl substituted with 1 to 2 hydroxyl groups; R ¹⁴ is selected from H, C _1- C ₄ alkyl and C _3- C ₆ cycloalkyl, wherein the C _1- C ₄ alkyl and C _3- C ₆ cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: C _1- C ₄ alkyl, halogen, -OH, -NR ¹⁵ R ¹⁶ , C _1- C ₂ alkoxy and C _1- C ₄ alkyl substituted with 1 to 2 hydroxyl groups; or R ¹³ and R ¹⁴ together with the nitrogen atom to which they are directly attached can form a ring which optionally contains additional N, O or S as a ring member and is optionally substituted with one to three groups selected from C _1- C R ₁₅ and R ¹⁶ are ^each _{independently} selected from H and C _{1 -} C ₄ alkyl; each R ¹⁷ is independently selected from H, C ₁ - C ₄ alkyl and C ₃ -C ₈ cycloalkyl, or R ¹⁷ is C _{1 -} C ₄ alkyl, which together with the nitrogen atom to which it is directly attached and the nitrogen atom from the pyrazole ring can form a 5-8 membered ring fused to the pyrazole ring; L ³ is a bond or a _straight chain or branched chain C _{1 -} C ₃ alkylene group; and

' indicates a single key or double keys. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (II):

wherein W, L, R ¹ , R ² , R ³ , t, R ⁴ and ^RB are as defined in claim 1. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ^RB is phenyl, pyridyl, thienyl or 5-8 membered cycloalkyl, wherein ^RB is optionally substituted with 1 to 3 ^R5 groups; ^R1 is selected from H, C1 _{- C3} alkyl and C1 _{- C3} alkyl substituted with 1 to 3 -OH groups; ^R2 is H; each ^R3, when present, is a substituent on the ring to which -LW is directly attached, wherein each ^R3 is independently selected from C1 _{- C3} alkyl; each ^R5 is independently selected from halogen, -CN, C1 _{- C3} alkoxy and C1 _{- C3} alkyl; W is ^cyclopropyl , wherein the cyclopropyl is _substituted with 1 to 3 groups independently selected from the following: _-SO2R10 , _-SO2NR14R10 ^{, -SO2} NR ¹³ R ¹⁴ and -SO ₂ N=CR ¹³ NR ¹³ R ¹⁴ ; R ¹⁰ is selected from C _1- C ₅ alkyl, C _1- C ₃ halogenalkyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members, 4-6 membered heterocycloalkyl containing one or two ring members independently selected from N, NH, NR ¹⁷ , O or S, and 4-6 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, wherein each R ¹⁰ is optionally substituted with 1 to 5 groups independently selected from the following: C _1- C ₄ alkyl, deuterium, C _1- C 3 halogenalkyl, 3-6 membered cycloalkyl, 5-6 membered heteroaryl having 1 to 4 heteroatoms independently selected from N, O and S as ring members _-4 -haloalkoxy, -OH, -CN, -OC(=O)R ¹⁴ , -L ³ OR ¹³ , -NR ¹³ R ¹⁴ , -NR ¹⁴ C(=O)R ¹³ , -NR ¹⁴ C(=O)OR ¹³ , -C(=O)NR ¹³ R ¹⁴ , -C(=O)OR ¹³ , (4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S), (4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S) and -C _{3 -} C ₅ cycloalkyl, wherein the C _{1 -} C ₄ alkyl, 4-7 membered heterocycloalkyl, 4-7 membered heterocycloalkyl and C _{3 -} The _C5 cycloalkyl is optionally further substituted with 1 to 3 groups independently selected from the following: halogen, -OR ¹³ and -NR ¹³ R ¹⁴ ; each R ¹³ is independently selected from H, C1 _{- C4} alkyl, 4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, 4-7 membered heterocycloalkyl containing 1 to 2 ring members independently selected from N, NH, NR ¹⁷ , O or S, and C3 _{- C6} cycloalkyl, wherein the C1 _{- C4} alkyl, heterocycloalkyl, heterocycloalkyl and C3- _C6 cycloalkyl are optionally substituted with 1 to 3 groups independently selected from the following: _C1 -C4 alkyl, heterocycloalkyl, heterocycloalkyl and C3 _- C6 cycloalkyl. ₄ alkyl, halogen, -OH, -NR ¹⁵ R ¹⁶ , -C(=O)OR ¹⁵ , C _1- C ₂ alkoxy and C _1- C ₄ alkyl substituted with 1 to 2 hydroxyl groups; R ¹⁴ is selected from H and C _1- C ₄ alkyl; wherein t, R ⁴ , L, R ¹¹ , R ¹² , R ¹³ , R ¹⁵ , R ¹⁶ , L ³ and

'As defined in claim 1. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure of formula (IIIa), formula (IIIb) or formula (IIIc):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the moiety W-L-- is selected from:

The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure of formula (Va):

The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R ¹ is H, methyl or methyl substituted by a -OH group; each R ⁵ is independently selected from Cl, F and -CN; L is CH ₂ or CH ₂ CH ₂ ; and R ¹⁰ is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, cyclopropyl, cyclobutyl, pyridyl, pyrazolyl, isobutyl

Azolyl, oxacyclobutane, tetrahydrofuranyl, tetrahydropyranyl, oxolinyl, piperidinyl, piperyl

R ¹⁰ is optionally substituted with 1 to 4 groups independently selected from the group consisting of methyl, ethyl, deuterium, -OCH ₃ , -OH, -OCHF ₂ , -CN, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHR ¹³ , -NHCH(=O), -NHC(=O)CH ₃ , -NHC(=O)OCH ₃ , -NHC(=O)CH ₂ NH ₂ , -NHC(=O)CH ₂ N(CH ₃ ) ₂ , -NHC(=O)CH(CH ₃ )NH ₂ , -NHC(=O)C(CH ₃ ) ₂ NH ₂ , -OCH ₂ CH ₂ OH, -OCH ₂ CH(CH ₃ )OH, -OCH ₂ CH(CH ₃ ) ₂ OH, -OCH(F)CH ₂ OH, -OCF ₂ CH ₂ OH, -OCH ₂ CH ₂ NH ₂ , -OCH ₂ CH(CH ₃ )NH ₂ , -OCH ₂ C(CH ₃ ) ₂ NH ₂ , -OCH ₂ CH ₂ NHCH ₃ , -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OCH(F)CH ₂ NH ₂ , -OCF ₂ CH ₂ NH ₂ , -CH ₂ OCH ₂ CH ₂ NH ₂ , -CH ₂ CH ₂ OH, -CH ₂ OH, -CH ₂ NH ₂ , -O-azetidinyl, -C(=O)NH ₂ , -C(=O)NHCH ₃ , -OC(=O)CH ₃ , cyclopropyl, azidocyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisopropyl

oxazolyl, wherein the methyl, ethyl, cyclopropyl, azidocyclobutanyl, pyrrolidinyl, oxolinyl, 6-oxa-3-azabicyclo[3.1.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl and 4,5-dihydroisoxazolyl are

The azole group may be further substituted with 1 to 3 groups independently selected from the group consisting of F, -OH, -OCH ₃ , and -NH ₂ . The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is selected from:

The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ¹ is H. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein each R ⁵ is independently selected from Cl, F, -CN, -OCH ₃ and methyl. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein each R ⁵ is independently selected from Cl and -CN. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein L is -CH ₂ - or -CH ₂ CH ₂ -. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein L is -CH ₂ -. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:

The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:

A pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. A compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof, for use in preparing a medicament, wherein the medicament is used to treat herpes virus infection. For use as claimed in claim 17, wherein the herpes virus is selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus including HSV-1 and HSV-2, herpes virus 6, human herpes virus 7 and Kaposi's sarcoma-associated herpes virus. For use as claimed in claim 17, wherein the drug is used to treat a disease induced, aggravated or accelerated by the herpes virus infection, wherein the disease is selected from the group consisting of: Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), chylous diarrhea and type 1 diabetes. For use as claimed in claim 17, wherein the medicament is used to treat atherosclerosis (AS), wherein AS is induced, aggravated or accelerated by infection with the herpes virus. The compound of claim 1 or a pharmaceutically acceptable salt thereof, which is:

1-(2-(2-bromoethoxy)ethyl)-N-(4-cyanobenzyl)-6-((1-((1-hydroxy-2-methylpropane-2-yl)sulfonyl)cyclopropyl)methyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide, or a pharmaceutically acceptable salt thereof. A use of a compound as claimed in any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating viral infection. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein R ⁴ is a C ₂ -C ₃ alkyl group substituted with 1 to 2 groups independently selected from -OH and R ¹⁰ . The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R ⁴ is substituted with -OH and optionally with methyl. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein W is ^SO2R10 . The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein R ¹⁰ is C ₁ -C ₄ alkyl substituted with 1 to 3 groups selected from C ₁ -C ₄ alkyl and -OH. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein in formula (Va), R ⁵ is a halogen group, and R ¹⁰ is a C _{1 -} C ₅ alkyl group substituted with two OH groups. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein in formula (Va), R ⁵ is -CN, and R ¹⁰ is a C _{1 -C 5} alkyl group substituted with two OH groups. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, which is a compound having a structure of formula (Vc),

or a pharmaceutically acceptable salt thereof. The compound of claim 29 or a pharmaceutically acceptable salt thereof, wherein each R ⁵ in formula (Vc) is a halogen group, and R ¹⁰ is a C _{1 -} C ₅ alkyl group substituted with two OH groups. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, which is a compound having a structure of formula (VIII) or a pharmaceutically acceptable salt thereof,

wherein R ¹⁰ is selected from: phenyl which is unsubstituted or substituted with one -CN; a 6-membered heteroaryl having 1-2 heteroatoms which is unsubstituted or substituted with one group selected from the group consisting of halogen, OH or NHC(=O)R ¹³ , each heteroatom being N, wherein R ¹³ is C ₁ -C ₄ alkyl; and C ₁ -C ₅ alkyl which is substituted with one C(=O)NR ¹³ R ¹⁴ or 2 or 3 OH, wherein R ¹³ is H or C ₁ -C ₄ alkyl, and R ¹⁴ is H or C ₁ -C ₄ alkyl. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein R ¹⁰ is an unsubstituted 6-membered heteroaryl group having 1-2 heteroatoms, each heteroatom being N. The compound of claim 31 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

A pharmaceutical composition comprising a compound as claimed in any one of claims 31 to 33 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. A compound as claimed in any one of claims 31 to 33 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound as claimed in any one of claims 31 to 33 or a pharmaceutically acceptable salt thereof for use in preparing a medicament, wherein the medicament is used to treat herpes virus infection. For use as claimed in claim 35, the herpes virus is selected from cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella-zoster virus (VZV), herpes simplex virus including HSV-1 and HSV-2, herpes virus 6, human herpes virus 7 and Kaposi's sarcoma-associated herpes virus. For use as claimed in claim 35, the drug is used to treat a disease induced, aggravated or accelerated by the herpes virus infection, wherein the disease is selected from the group consisting of: Alzheimer's disease, chronic fatigue syndrome (CFS), systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), inflammatory bowel disease (IBD), atherosclerosis (AS), chylous diarrhea and type 1 diabetes. A use of a compound as claimed in any one of claims 31 to 33 or a pharmaceutically acceptable salt thereof for preparing a medicament for treating viral infection. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:

A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: